KR20080038380A - Quinoline derivatives as antimicrobials - Google Patents

Abstract

Compounds of formula (Ia) or (Ib), their pharmaceutically acceptable acid or base addition salts, quaternary amines, stereochemical isomers, tautomers or N, for the manufacture of a medicament for the treatment of bacterial infections except mycobacterial infection Uses in the form of oxides are disclosed:

Where

R ¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl;

p is 1, 2 or 3;

의 래디칼이고;R ² is hydrogen; Alkyl; Hydroxy; Mercapto; Optionally substituted alkyloxy; Alkyloxyal killoxy; Alkylthio; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted; Ar; Het or expression

Is a radical of;

R ³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;

q is 0, 1, 2, 3 or 4;

X is a direct bond or CH ₂ ;

R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl;

R ⁴ and R ⁵ may be bonded together, including the N to which they are attached;

의 래디칼이며; R ⁶ is hydrogen or

Is a radical of;

R ⁷ is hydrogen, alkyl, Ar or Het;

R ⁸ is hydrogen or alkyl;

R ⁹ is oxo;

R ⁸ and R ⁹ together form a radical —CH═CH—N =.

Description

Quinoline derivatives as antibacterial agents {QUINOLINE DERIVATIVES AS ANTIBACTERIAL AGENTS}

The present invention relates to the use of quinoline derivatives for the manufacture of a medicament for the treatment of bacterial infections.

The problem of resistance to first-generation antibiotics is on the rise. Some important examples include penicillin-resistant Streptococcus pneumoniae , vancomycin-resistant enterococci , methicillin-resistant Staphylococcus aureus , and multi-resistant salmonellae . do.

The consequences of antibiotic resistance are serious. Infection with resistant microorganisms renders them unresponsive to treatment, leading to prolonged illness and increased risk of death. Treatment failures also increase the duration of infection, increasing the number of infected populations in the community, which puts the general population at risk of contact with resistant strain infections. Hospitals are a major contributor to antimicrobial resistance issues worldwide. The combination of highly susceptible patients, extensive and persistent antimicrobial use, and cross infection leads to infection of highly resistant bacterial pathogens.

Self-treatment of antimicrobial agents is another major factor contributing to resistance. Self-treatment of antimicrobial agents may be unnecessary and often may be inappropriately dosed or may not contain an appropriate amount of active drug.

Patient compliance with recommended treatment is another major factor. The patient may forget to take the drug, may stop his treatment when the condition begins to improve, or may not be able to go through the whole process, creating an ideal environment for adapting rather than killing the microorganisms.

With the advent of multiple antibiotic resistance, doctors faced infections without effective treatment. The morbidity, mortality, and financial costs of these infections are becoming obstacles to health care systems worldwide.

Thus, new compounds are desired for treating bacterial infections, particularly for treating infections caused by resistant strains.

Substituted quinolines are disclosed in US (US) 5,965,572 for the treatment of antibiotic resistant infections and in WO 00/34265 for inhibiting bacterial microbial growth.

WO 2004/011436, WO2005 / 070924, WO2005 / 070430 and WO2005 / 075428 describe certain substituted quinoline derivatives that show activity against mycobacteria, in particular Mycobacterium tuberculosis . One particular compound of these substituted quinoline derivatives is described in Science (2005), 307, 223-227.

None of these publications discloses the substituted quinoline derivatives according to the present invention.

[Summary of invention]

Accordingly, the present invention provides compounds of formulas (Ia) and (Ib), pharmaceutically acceptable acid or base addition salts, quaternary amines, stereochemical isomers, toto, for the preparation of medicaments for the treatment of bacterial infections except mycobacterial infections. To a mer or N-oxide form:

Where

R ¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl;

p is an integer of 1, 2 or 3;

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)에 의해 임의로 치환된 알킬옥시; 알킬옥시알킬옥시; 알킬티오; 모노 또는 디(알킬)아미노(여기에서, 알킬은 각각 알킬옥시, Ar, Het, 모르폴리닐 및 2-옥소피롤리디닐로 구성된 그룹중에서 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환될 수 있음); Ar; Het 또는 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)이고;R ² is hydrogen; Alkyl; Hydroxy; Mercapto; Amino or mono or di (alkyl) amino or formula

Alkyloxy optionally substituted by radicals of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an optional bond; Alkyloxyalkyloxy; Alkylthio; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two substituents independently selected from the group consisting of alkyloxy, Ar, Het, morpholinyl and 2-oxopyrrolidinyl, respectively has exist); Ar; Het or expression

Is a radical of which Z is CH ₂ , CH—R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an arbitrary bond;

R ³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;

q is an integer of 0, 1, 2, 3 or 4;

X is a direct bond or CH ₂ ;

R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl;

R ⁴ and R ⁵ together with N, to which they are attached, are each alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl or pyri Pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, optionally substituted by midinyl, Forms a radical selected from the group consisting of triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Can do it;

의 래디칼이고, 여기에서, s는 0, 1, 2, 3 또는 4의 정수이며, r은 1, 2, 3, 4 또는 5의 정수이고, R¹¹은 수소, 할로, 할로알킬, 하이드록시, Ar, 알킬, 알킬옥시, 알킬티오, 알킬옥시알킬, 알킬티오알킬, Ar-알킬 또는 디(Ar)알킬이거나, 두개의 인접한 R¹¹ 래디칼은 함께, 이들이 결합된 페닐 환과 나프틸을 형성할 수 있고;R ⁶ is hydrogen or

Is a radical of wherein s is an integer of 0, 1, 2, 3 or 4, r is an integer of 1, 2, 3, 4 or 5, R ¹¹ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl, or two adjacent R ¹¹ radicals together may form naphthyl with the phenyl ring to which they are attached ;

R ⁷ is hydrogen, alkyl, Ar or Het;

R ⁸ is hydrogen or alkyl;

R ⁹ is oxo;

R ⁸ and R ⁹ together form a radical —CH═CH—N =;

R ¹⁰ is hydrogen, alkyl, hydroxyl, aminocarbonyl, mono- or di (alkyl) aminocarbonyl, Ar, Het, alkyl substituted by 1 or 2 Het, or substituted by 1 or 2 Ar Alkyl, Het-C (= 0)-or Ar-C (= 0)-;

Alkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein each carbon atom may be optionally substituted by hydroxy, alkyloxy or oxo;

Ar is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, alkylcarbonyl, aminocarbonyl, mor Selected from the group consisting of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl optionally substituted by one, two or three substituents independently selected from the group consisting of polyyl and mono- or dialkylaminocarbonyl Homocycle;

Het is N -phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, Monocyclic heterocycles selected from the group consisting of pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothia Bicyclic heterocycle selected from the group consisting of zolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxylyl and benzo [1,3] dioxolyl ego; Each monocyclic and bicyclic heterocycle may be optionally substituted on the carbon atom by 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy, alkyl and alkyloxy;

Halo is a substituent selected from the group consisting of fluoro, chloro, bromo and iodo;

Haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein at least one carbon atom is substituted by at least one halo atom,

only,

When R ⁷ is hydrogen,

Radical

May be present at the 4 position of the quinoline ring.

The invention also relates to methods of treating bacterial infections other than mycobacteria in these, including administering to a mammal, in particular a warm blooded mammal, more particularly a human, an effective amount of a compound of the invention.

A compound of formula (Ib) wherein R ⁸ is oxo is a compound of formula (Ia) and (Ib) in that it has a tautomer (keto-enol tautomerization) relationship with a compound of formula (Ia) where R ² is hydroxy Are interrelated.

Description of the Invention

In the context of the present specification, alkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms bonded to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms (where each carbon atom is optionally hydroxy, alkyloxy or oxo May be substituted). Preferably, alkyl is methyl, ethyl or cyclohexylmethyl. Useful embodiments of alkyl in all definitions used above and below refer to C ₁ which represents straight or branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-methylethyl, pentyl, hexyl, and the like. _-6 alkyl. Preferred subgroups of C _1-6 alkyl are C _1-4 alkyl representing straight or branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-methyl-ethyl and the like.

In the context of the present specification, Ar is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl , Groups consisting of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, optionally substituted with one, two or three substituents each independently selected from the group consisting of morpholinyl and mono- or dialkylaminocarbonyl Homocycle selected from Preferably, Ar is naphthyl or phenyl optionally substituted with one or two halo substituents, respectively.

In the context of the present specification, Het is N -phenoxypiperidinyl, pyridinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyri Monocyclic heterocycles selected from the group consisting of diyl, pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [ Bicyclic heterocycle selected from the group consisting of 1,4] dioxylyl and benzo [1,3] dioxolyl; Each monocyclic and bicyclic heterocycle may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, hydroxy, alkyl and alkyloxy. Preferably, Het is thienyl, furanyl or pyridyl, most preferably furanyl.

In the context of this specification, halo is a substituent selected from fluoro, chloro, bromo and iodo groups and haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms or 3 to 6 carbon atoms Cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms bonded to straight or branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms; Wherein at least one carbon atom is substituted with at least one halo atom. Preferably, halo is bromo, fluoro or chloro and preferably haloalkyl is mono- or polyhalosubstituted C _1-6 alkyl, for example methyl having one or more fluoro atoms, for example difluoro PolyhaloC _1-6 alkyl as defined by methyl or trifluoromethyl, 1,1-difluoro-ethyl and the like. When a plurality of halo atoms are bonded to an alkyl group within the definition of haloalkyl or polyhaloC _1-6 alkyl they may be the same or different.

In the context of the present specification, the quinoline moiety of the compound of formula (la) or (lb) is numbered as follows:

는 퀴놀린 부분의 임의의 허용 위치에 존재할 수 있다.Radical,

May be present at any acceptable position of the quinoline moiety.

In the definition of Het, this includes all possible isomers of the heterocycle, for example pyrrolyl includes 1 H -pyrrolyl and 2 H -pyrrolyl.

Ar or Het listed in the definitions of substituents of compounds of formula (Ia) or (Ib) mentioned before or hereinafter, if not otherwise specified, is optionally represented by formula (Ia) or (Ib) via any ring carbon or heteroatom ) May be attached to the rest of the molecule. Thus, for example, when Het is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

Lines drawn from the substituents into the ring system indicate that the bond may be bonded to any suitable ring atom.

Pharmaceutically acceptable acid addition salts are intended to include therapeutically active non-toxic acid addition salt forms which the compounds of formula (la) or (lb) may form. Base forms of the compounds according to formula (la) or (lb) may be selected from suitable acids, for example inorganic acids such as hydrochloric acid, in particular hydrochloric acid, hydrobromic acid; Sulfuric acid; nitric acid; And phosphoric acid; Organic acids such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene The acid addition salts can be obtained by treatment with sulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

Compounds according to formula (la) or (lb), including acidic protons, can be converted to their therapeutically active non-toxic base addition salt forms by treatment with appropriate organic and inorganic bases. Suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium, calcium salts, salts with organic bases such as benzatin, N-methyl-D-glucamine, Hydrabamine salts, and salts with amino acids such as arginine and lysine.

In contrast, acid or base addition salt forms can be converted to the free form by treatment with an appropriate base or acid.

As used herein, the term addition salt also includes solvates which the compounds according to formula (Ia) or (Ib) and salts thereof can form. Such solvates are, for example, hydrates and alcoholates.

The term "quaternary amine" as used above refers to basic quaternizing agents of compounds of formula (I) with suitable quaternizing agents, such as, for example, optionally substituted alkyl halides, arylalkyl halides, alkylcarbonyl halides, arcarbonyl halides, Hetalkyl It is defined as quaternary ammonium salts which can be formed by compounds of formula (I) by reaction of halides or Hetcarbonyl halides such as methyliodide or benzyl iodide. Preferably, Het is a monocyclic heterocycle selected from furanyl or thienyl; Or a bicyclic heterocycle selected from benzofuranyl or benzothienyl; Each monocyclic and bicyclic heterocycle may be optionally substituted by one, two or three substituents independently selected from the group consisting of halo, alkyl and Ar, respectively. Preferably, the quaternizing agent is an alkyl halide. Other reactants with good leaving groups such as alkyl trifluoromethanesulfonate, alkyl methanesulfonate and alkyl p-toluenesulfonate can also be used. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. Selected counterions can be introduced using ion exchange resins.

Some of the compounds of formula (la) or (lb) and intermediate compounds necessarily have at least two stereogenic centers that can lead to at least one stereochemically different structure in their structure.

The term “stereoisomer” as used above or hereinafter means all possible stereoisomers which a compound of formula (la) or (lb) may have. Unless otherwise stated or indicated, the chemical designation of a compound refers to a mixture of all possible stereoisomers, which mixtures include diastereomers and enantiomers of basic molecular structure. In particular, the stereogenic center may have an R- or S-configuration; Bivalent cyclic (partially) saturated radicals are substituents on the cis (cis) - can have a coordination-or trans (trans). Stereochemically isomeric forms of the compounds of formula (la) or (lb) are expressly intended to be included within the scope of this invention.

According to the CAS nomenclature provisions, if there are two stereocenters of known absolute configuration, the R or S descriptor (based on the Cahn-Ingold-Prelog alignment rule) is designated as the lowest numbered chiral center that is the reference center. The coordination of the second stereoscopic center is expressed using the relative descriptors [R *, R *] or [R *, S *] (where R * is always specified as the reference center and [R *, R *] is Centers having the same chirality and [R *, S *] represent centers having different chirality). For example, if the lowest numbered chiral center in a molecule has an S configuration and the second center is R, the steric descriptors are described as S- [R *, S *]. When "α" and "β" are used, the position of the priority substituent on the asymmetric carbon atom of the ring system with the lowest ring number is always "α" of the mean plane determined by the ring system. Present in the position. The position of the most preferred substituent on another asymmetric carbon atom in the ring system with respect to the position of the most preferred substituent on the reference atom is "α" when present on the same side of the average plane determined by the ring system, or by the ring system When present on the other side of the determined mean plane, it is named "β".

When referring to specific stereoisomers, this means that the form is substantially free of other isomer (s), that is, less than 50%, preferably less than 20%, more preferably less than 10% with other isomer (s). , Even more preferably less than 5%, even more preferably less than 2% and most preferably less than 1%. Thus, when a compound of formula (la) or (lb) is specified, for example as (S), this means that the compound is substantially free of the (R) isomer.

The compounds of formulas (la) and (lb) can be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another according to known partitioning procedures. The racemic compounds of formulas (la) and (lb) can be converted into the corresponding diastereomeric salt forms by reaction with the appropriate chiral acid. The diastereomeric salt form is then separated, for example by selective or fractional crystallization, from which the enantiomer is released by alkali. Another method of separating the enantiomeric forms of the compounds of formulas (la) and (lb) includes liquid chromatography using chiral stationary phases. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of the appropriate starting materials if the reaction takes place stereospecifically. Preferably, if specific stereoisomers are desired, the compounds may be synthesized by stereospecific methods of preparation. These methods advantageously utilize enantiomerically pure starting materials.

Tautomeric forms of the compounds of formula (la) or (lb) mean, for example, comprising compounds of formula (la) or (lb) in which the enol group is converted to a keto group (keto-enol tautomerized). .

The N -oxide form of the compound according to formula (Ia) or (Ib) is characterized by the formula (Ia) or (Ib) in which one or several tertiary nitrogen atoms are oxidized to the so-called N -oxides, in particular the oxidized N -oxides of the amine radicals It means containing a compound of).

The invention also encompasses derivative compounds of the pharmacologically active compounds according to the invention (aka "prodrugs") which are degraded in vivo and converted into the compounds according to the invention. Prodrugs generally (but not always) have lower potency at the target receptor than the compounds they degrade. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, if the desired compound is poorly soluble, it may have poor or undesirably short plasma half-life through mucosal epithelial cells. For discussion of prodrugs, see Stella, VJ et al ., "Prodrugs", Drug Delivery Systems , 1985, pp. 112-176 and Drugs , 1985, 29 , pp. 455-473, for more information.

Prodrug forms of pharmacologically active compounds according to the invention are generally compounds of formula (Ia) or (Ib) having esterified or amidated acid groups, pharmaceutically acceptable acid or base addition salts, stereochemically In the form of isomers, tautomers and N -oxides. The esterified acid group includes a group of the formula -COOR ^X , wherein R ^X is one of C _1-6 alkyl, phenyl, benzyl or the following groups:

The amidated group comprises a group of the formula -CONR ^y R ^z , wherein R ^y is H, C _1-6 alkyl, phenyl or benzyl and R ^z is -OH, H, C _1-6 alkyl, phenyl or Benzyl.

Compounds according to the invention having amino groups can be derivatized with aldehydes such as ketones or formaldehyde to form Mannich bases. This base will be hydrolyzed to first order reaction in aqueous solution.

As used herein, the term “compound of formula (la) or (lb)” is always intended to include its N -oxide forms, salts, quaternary amines, tautomers or stereochemically isomers as well. Of particular interest are the compounds of formula (Ia) or (Ib) which are stereochemically pure.

Important embodiments of the present invention

R ¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl;

p is an integer of 1, 2 or 3;

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)에 의해 임의로 치환된 알킬옥시; 알킬옥시알킬옥시; 알킬티오; 모노 또는 디(알킬)아미노(여기에서, 알킬은 각각 알킬옥시, Ar, Het, 모르폴리닐 및 2-옥소피롤리디닐으로 구성된 그룹중에서 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환될 수 있음); Het 또는 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)이며;R ² is hydrogen; Alkyl; Hydroxy; Mercapto; Amino or mono or di (alkyl) amino or formula

Alkyloxy optionally substituted by radicals of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an optional bond; Alkyloxyalkyloxy; Alkylthio; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two substituents independently selected from the group consisting of alkyloxy, Ar, Het, morpholinyl and 2-oxopyrrolidinyl, respectively has exist); Het or expression

Is a radical of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an arbitrary bond;

R ³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;

q is an integer of 0, 1, 2, 3 or 4;

X is a direct bond;

R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl;

R ⁴ and R ⁵ together with N, to which they are attached, are each alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl or pyri Pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, optionally substituted by midinyl, Forms a radical selected from the group consisting of triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Can do it;

의 래디칼이고, 여기에서, s는 0, 1, 2, 3 또는 4의 정수이며, r은 1, 2, 3, 4 또는 5의 정수이고, R¹¹은 수소, 할로, 할로알킬, 하이드록시, Ar, 알킬, 알킬옥시, 알킬티오, 알킬옥시알킬, 알킬티오알킬, Ar-알킬 또는 디(Ar)알킬이거나, 두개의 인접한 R¹¹ 래디칼은 함께, 이들이 결합된 페닐 환과 나프틸을 형성할 수 있고;R ⁶ is an expression

Is a radical of wherein s is an integer of 0, 1, 2, 3 or 4, r is an integer of 1, 2, 3, 4 or 5, R ¹¹ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl, or two adjacent R ¹¹ radicals together may form naphthyl with the phenyl ring to which they are attached ;

R ⁷ is hydrogen, alkyl, Ar or Het;

R ⁸ is hydrogen or alkyl;

R ⁹ is oxo;

R ⁸ and R ⁹ together form a radical —CH═CH—N =;

R ¹⁰ is hydrogen, alkyl, aminocarbonyl, mono- or di (alkyl) aminocarbonyl, Ar, Het, alkyl substituted by 1 or 2 Het, or alkyl or Het substituted by 1 or 2 Art -C (= 0)-;

Alkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein each carbon atom may be optionally substituted by hydroxy, alkyloxy or oxo;

Ar is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, alkylcarbonyl, aminocarbonyl, mor Selected from the group consisting of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl optionally substituted by one, two or three substituents independently selected from the group consisting of polyyl and mono- or dialkylaminocarbonyl Homocycle;

Het is N -phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, Monocyclic heterocycles selected from the group consisting of pyrazinyl and pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-di A bicyclic heterocycle selected from the group consisting of hydrobenzo [1,4] dioxylyl and benzo [1,3] dioxolyl; Each monocyclic and bicyclic heterocycle may be optionally substituted on the carbon atom by 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy, alkyl and alkyloxy;

Halo is a substituent selected from the group consisting of fluoro, chloro, bromo and iodo;

Haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein at least one carbon atom is substituted by at least one halo atom, a compound of formula (Ia) or (Ib), a pharmaceutically acceptable acid or base addition salt, quaternary amine, stereochemical isomer, tautomer or N-oxide thereof It's about form.

Preferably, the present invention

Formulas mentioned above as useful embodiments, wherein R ¹¹ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl A compound of (la) or (lb) or any subgroup thereof.

Preferably the present invention when the R ⁶ different from hydrogen, R, if ⁷ is hydrogen, the R ⁷ other than hydrogen, R ⁶ is of formula (Ia) or (Ib) mentioned above as hydrogen, useful embodiments To a compound or any subgroup thereof.

Preferably, the present invention relates to a compound of formula (la) or (lb) mentioned above or any subgroup thereof as useful embodiments wherein R ⁷ is hydrogen when R ⁶ is not hydrogen.

Preferably, the present invention relates to the compounds of formula (la) or (lb) mentioned above or any subgroup thereof as useful embodiments wherein R ⁶ is hydrogen when R ⁷ is not hydrogen.

Preferably, the present invention

R ¹ is hydrogen, halo, cyano, Ar, Het, alkyl or alkyloxy;

p is an integer of 1, 2 or 3;

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)에 의해 임의로 치환된 알킬옥시; 알킬옥시알킬옥시; 알킬티오; 모노 또는 디(알킬)아미노; Ar; Het 또는 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)이며;R ² is hydrogen; Alkyl; Hydroxy; Amino or mono or di (alkyl) amino or formula

Alkyloxy optionally substituted by radicals of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an optional bond; Alkyloxyalkyloxy; Alkylthio; Mono or di (alkyl) amino; Ar; Het or expression

Is a radical of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an arbitrary bond;

R ³ is alkyl, Ar, Ar-alkyl or Het;

q is an integer of 0, 1, 2 or 3;

X is a direct bond or CH ₂ ;

R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl;

R ⁴ and R ⁵ together with N, to which they are attached, are pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl, morpholi together optionally substituted by alkyl and pyrimidinyl, respectively; A radical selected from the group consisting of nil and thiomorpholinyl;

의 래디칼이고, 여기에서, s는 0, 1, 2, 3 또는 4의 정수이며, r은 1, 2, 3, 4 또는 5의 정수이고, R¹¹은 수소, 할로 또는 알킬이거나, 두개의 인접한 R¹¹ 래디칼은 함께, 이들이 결합된 페닐 환과 나프틸을 형성할 수 있고, 바람직하게 R¹¹은 수소, 할로 또는 알킬이며;R ⁶ is hydrogen or

Is a radical of wherein s is an integer of 0, 1, 2, 3 or 4, r is an integer of 1, 2, 3, 4 or 5, and R ¹¹ is hydrogen, halo or alkyl, or two adjacent R ¹¹ radicals together may form naphthyl with the phenyl ring to which they are attached, preferably R ¹¹ is hydrogen, halo or alkyl;

r is an integer of 1;

R ⁷ is hydrogen or Ar;

R ⁸ is hydrogen or alkyl;

R ⁹ is oxo;

R ⁸ and R ⁹ together form a radical —CH═CH—N =;

Alkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein each carbon atom may be optionally substituted by hydroxyl;

Ar is phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl, each optionally substituted by one, two or three substituents independently selected from the group consisting of halo, haloalkyl, cyano, alkyloxy and morpholinyl A homocycle selected from the group consisting of;

Het is N -phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, Monocyclic heterocycles selected from the group consisting of pyrazinyl and pyridazinyl; Or quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothia Bicyclic heterocycle selected from the group consisting of zolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxylyl and benzo [1,3] dioxolyl ego; Each monocyclic and bicyclic heterocycle may be optionally substituted on the carbon atom by 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy, alkyl and alkyloxy;

Halo is a substituent selected from the group consisting of fluoro, chloro and bromo;

Haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; One or more carbon atoms herein relates to compounds of formula (la) and (lb) substituted by one or more halo atoms.

Preferably, the present invention relates to a compound of formula (la) or (lb) mentioned above as a useful embodiment or any subgroup thereof, wherein R ¹ is hydrogen, halo, Ar, Het, alkyl or alkyloxy. . More preferably, R ¹ is hydrogen, halo, alkyl or Het. Even more preferably, R ¹ is hydrogen, halo or Het. Even more preferably, R ¹ is halo, especially bromo.

Preferably, the present invention relates to the compounds of formula (la) or (lb) mentioned above or any subgroup thereof as useful embodiments wherein p is one.

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)에 의해 임의로 치환된 알킬옥시; 모노 또는 디(알킬)아미노(여기에서, 알킬은 각각 알킬옥시 및 Ar로 구성된 그룹중에서 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환될 수 있음); Ar; Het 또는 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O, S 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, 점선은 임의 결합임)인, 유용한 구체예로서 상기 언급된 화학식 (Ia) 또는 (Ib)의 화합물 또는 이들의 임의의 하위 그룹에 관한 것이다. 보다 바람직하게, R²는 알킬옥시; Het; Ar; 알킬; 모노 또는 디(알킬)아미노(여기에서, 알킬은 각각 알킬옥시 및 Ar로 구성된 그룹중에서 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환될 수 있음); 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O 또는 N-R¹⁰이며, t는 1 또는 2의 정수임); 아미노 또는 모노 또는 디(알킬)아미노 또는 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O 또는 N-R¹⁰이며, t는 1 또는 2의 정수임)에 의해 임의로 치환된 알킬옥시이다. 보다 더 바람직하게, R²는 알킬옥시; Het; Ar; 모노 또는 디(알킬)아미노(여기에서, 알킬은 1 또는 2개의 Ar 치환체에 의해 임의로 치환될 수 있음); 식

의 래디칼(여기에서, Z는 N-R¹⁰이며, t는 2의 정수임); 아미노 또는 모노 또는 디(알킬)아미노 또는 식

의 래디칼(여기에서, Z는 CH₂이며, t는 2의 정수임)에 의해 임의로 치환된 알킬옥시이다. 가장 바람직하게, R²는 알킬옥시, 예를 들어 메틸옥시; Het; 또는 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O 또는 N-R¹⁰이며, t는 1 또는 2의 정수임)이고, 특히 R²는 알킬옥시이다.Preferably, the present invention provides that R ² is hydrogen; Alkyl; Amino or mono or di (alkyl) amino or formula

Alkyloxy optionally substituted by radicals of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an optional bond; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two substituents independently selected from the group consisting of alkyloxy and Ar, respectively; Ar; Het or expression

Is a radical of the formula wherein Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dashed line is an arbitrary bond. A compound of Ia) or (Ib) or any subgroup thereof. More preferably, R ² is alkyloxy; Het; Ar; Alkyl; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two substituents independently selected from the group consisting of alkyloxy and Ar, respectively; expression

Radicals, wherein Z is CH ₂ , CH—R ¹⁰ , O or NR ¹⁰ , and t is an integer of 1 or 2; Amino or mono or di (alkyl) amino or formula

Is alkyloxy optionally substituted by radicals of which Z is CH ₂ , CH-R ¹⁰ , O or NR ¹⁰ and t is an integer of 1 or 2. Even more preferably, R ² is alkyloxy; Het; Ar; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two Ar substituents; expression

Radicals, wherein Z is NR ¹⁰ and t is an integer of 2; Amino or mono or di (alkyl) amino or formula

Is alkyloxy optionally substituted by radicals of which Z is CH ₂ and t is an integer of 2. Most preferably, R ² is alkyloxy, for example methyloxy; Het; Or expression

Is a radical of which Z is CH ₂ , CH—R ¹⁰ , O or NR ¹⁰ , and t is an integer of 1 or 2, in particular R ² is alkyloxy.

Preferably, the present invention is a useful sphere wherein R ³ is naphthyl, phenyl or Het, each of which is optionally substituted by one or two substituents, which substituents are preferably halo or haloalkyl, most preferably halo By way of example, it relates to the compounds of formula (la) or (lb) mentioned above or any subgroup thereof. More preferably, R ³ is naphthyl, phenyl, 3,5-dihalophenyl, 1,6-dihalophenyl, thienyl, furanyl, benzofuranyl, pyridyl. Even more preferably, R ³ is naphthyl, phenyl, 3,5-dihalophenyl, thienyl, furanyl or benzofuranyl. Most preferably, R ³ is optionally substituted phenyl, for example 3,5-dihalophenyl or naphthyl.

Preferably, the present invention relates to a compound of formula (la) or (lb) or any subgroup thereof as mentioned above as a useful embodiment, wherein q is 0, 1 or 2. More preferably, q is 1.

Preferably, the invention relates to the above-mentioned formulas (Ia) or (Ib) as useful embodiments, wherein R ⁴ and R ⁵ are each independently hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, most preferably methyl. ) Or any subgroup thereof.

Preferably, the invention provides that R ⁴ and R ⁵ together, including N to which they are attached, are each alkyl, halo, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl or alkylthioalkyl, preferably alkyl Mentioned above as a useful embodiment, forming a radical selected from the group consisting of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, most preferably optionally substituted by methyl or ethyl A compound of formula (la) or (lb) or any subgroup thereof.

의 래디칼이고, 여기에서, s는 0, 1 또는 2, 바람직하게는 0 또는 1의 정수이며, r은 1 또는 2, 바람직하게는 1의 정수이고, R¹¹은 수소, 할로 또는 알킬, 바람직하게는 수소 또는 알킬인, 유용한 구체예로서 상기 언급된 화학식 (Ia) 또는 (Ib)의 화합물 또는 이들의 임의의 하위 그룹에 관한 것이다. 보다 바람직하게, R⁶은 식

의 래디칼이다. 가장 바람직하게, R⁶은 벤질 또는 페닐이다. 바람직하게, r은 1이고, R¹¹은 수소이다.Preferably, the present invention provides that R ⁶ is hydrogen or

Is a radical, wherein s is 0, 1 or 2, preferably an integer of 0 or 1, r is an integer of 1 or 2, preferably 1, and R ¹¹ is hydrogen, halo or alkyl, preferably Relates to a compound of formula (la) or (lb) mentioned above or any subgroup thereof, as useful embodiments, wherein is hydrogen or alkyl. More preferably, R ⁶ is a formula

Is a radical. Most preferably, R ⁶ is benzyl or phenyl. Preferably, r is 1 and R ¹¹ is hydrogen.

Preferably, the present invention relates to a compound of formula (la) or (lb) or any subgroup thereof mentioned above as a useful embodiment, wherein R ⁷ is hydrogen, alkyl or Ar. More preferably, R ⁷ is hydrogen or Ar, in particular hydrogen or phenyl. Most preferably, R ⁷ is hydrogen.

Only in the case of compounds of formula (Ib), preferably, the invention relates to the above-mentioned formulas (Ia) or (Ib) as useful embodiments wherein R ⁸ is alkyl or hydrogen, preferably hydrogen and R ⁹ is oxygen And to any subgroup thereof.

Preferably, the present invention is useful, wherein R ¹⁰ is hydrogen, alkyl, hydroxyl, alkyl substituted by 1 or 2 Het, or alkyl substituted by 1 or 2 Ar, Het-C (= 0)-. As an embodiment it relates to a compound of formula (la) or (lb) mentioned above or any subgroup thereof. More preferably, R ¹⁰ is alkyl or Ar. Most preferably, R ¹⁰ is hydroxyl, Het, alkyl substituted by one Het or alkyl substituted by one Ar

Preferably, the compounds of the invention or any subgroups thereof mentioned above as useful embodiments are compounds of formula (Ia), pharmaceutically acceptable acid or base addition salts thereof, quaternary amines, stereochemical isomers, tautomers Or N -oxide form.

Preferably, the present invention relates to the compounds of the invention or any subgroups thereof mentioned above as useful embodiments, wherein X is a direct bond.

Preferably, the present invention relates to the compounds of the invention or any subgroups thereof mentioned above as useful embodiments, wherein X is CH ₂ .

Preferably, the present invention relates to the compounds of the present invention or any subgroups of those mentioned above as useful embodiments, wherein R ³ is not unsubstituted phenyl when R ² is Het.

래디칼이 4, 5 또는 8, 특히 8번에 위치한, 유용한 구체예로서 상기 언급된 본 발명의 화합물 또는 이들의 임의의 하위 그룹에 관한 것이다.Preferably, the present invention

As a useful embodiment, the radical is located at 4, 5 or 8, in particular 8, relates to the compounds of the invention mentioned above or any subgroup thereof.

Useful compound groups are

R ¹ is hydrogen, halo, Ar, alkyl or alkyloxy;

p is 1;

R ² is hydrogen, alkyloxy or alkylthio;

R ³ is naphthyl, phenyl or thienyl, optionally substituted by one or two substituents selected from the group consisting of halo and haloalkyl, respectively;

q is 0, 1, 2 or 3;

R ⁴ and R ⁵ are each independently hydrogen or alkyl;

R ⁴ and R ⁵ together with N to which they are attached may form a radical selected from the group consisting of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl;

R ⁶ is hydrogen, alkyl or halo;

r is 1;

R ⁷ is hydrogen

A compound of formula (la) or (lb), preferably (la), or a pharmaceutically acceptable acid or base addition salt, quaternary amine, stereochemical isomer, tautomer or N -oxide form thereof.

Useful compound groups are also

R ¹ is hydrogen, halo, alkyl or Het, where Het is preferably pyridyl;

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O 또는 N-R¹⁰, 바람직하게는 CH₂이며, t는 1 또는 2의 정수이고, R¹⁰은 수소, 알킬, 하이드록실, 1 또는 2개의 Het에 의해 치환된 알킬, 1 또는 2개의 Ar에 의해 치환된 알킬, Het-C(=O)-, 바람직하게는 수소임)에 의해 임의로 치환된 알킬옥시; Ar; Het; 식

의 래디칼(여기에서, Z는 CH₂, CH-R¹⁰, O 또는 N-R¹⁰이며, t는 1 또는 2의 정수이고, R¹⁰은 수소, 알킬, 하이드록실, 1 또는 2개의 Het에 의해 치환된 알킬, 1 또는 2개의 Ar에 의해 치환된 알킬, Het-C(=O)-임)이고;R ² is alkyl; Mono or di (alkyl) amino or a formula

Radicals, wherein Z is CH ₂ , CH-R ¹⁰ , O or NR ¹⁰ , preferably CH ₂ , t is an integer of 1 or 2, and R ¹⁰ is hydrogen, alkyl, hydroxyl, 1 or 2 Alkyl substituted by Het, alkyl substituted by 1 or 2 Ar, alkyloxy optionally substituted by Het-C (= 0)-, preferably hydrogen); Ar; Het; expression

Radicals, wherein Z is CH ₂ , CH-R ¹⁰ , O or NR ¹⁰ , t is an integer of 1 or 2, and R ¹⁰ is hydrogen, alkyl, hydroxyl, substituted by 1 or 2 Het Alkyl, alkyl substituted by 1 or 2 Ar, wherein Het-C (= 0)-;

R ³ is Ar, preferably phenyl, naphthyl or Het, preferably thienyl, furanyl, pyridyl, benzofuranyl, and Ar and Het are each optionally substituted by 1 or 2 substituents, preferably halo Substituted;

R ⁴ and R ⁵ are each alkyl, preferably methyl;

R ⁶ is hydrogen, phenyl, benzyl or 4-methylbenzyl;

R ⁷ is hydrogen or phenyl;

R ⁸ is hydrogen;

R ⁹ is oxo

A compound of formula (la) or (lb), preferably (la), or a pharmaceutically acceptable acid or base addition salt, quaternary amine, stereochemical isomer, tautomer or N -oxide form thereof.

Especially,

R ¹ is hydrogen, halo or Het, where Het is preferably pyridyl;

의 래디칼(여기에서, Z는 CH₂이며, t는 1 내지 2의 정수이임)에 의해 임의로 치환된 알킬옥시; 모노 또는 디(알킬)아미노(여기에서, 알킬은 1 또는 2개의 Ar에 의해 치환됨); 식

의 래디칼(여기에서, Z는 N-R¹⁰이며, t는 2의 정수임) 또는 Het이고;R ² is mono or di (alkyl) amino or a formula

Alkyloxy optionally substituted by radicals of which Z is CH ₂ and t is an integer from 1 to 2; Mono or di (alkyl) amino, wherein alkyl is substituted by 1 or 2 Ar; expression

Is a radical of which Z is NR ¹⁰ and t is an integer of 2 or Het;

R ³ is Ar, preferably phenyl, naphthyl or Het, preferably thienyl, furanyl or benzofuranyl, and Ar and Het are each optionally substituted by 1 or 2 substituents, preferably halo;

R ⁴ and R ⁵ are each alkyl, preferably methyl;

R ⁶ is hydrogen, phenyl or benzyl, in particular phenyl or benzyl;

R ⁷ is hydrogen

Or a pharmaceutically acceptable acid or base addition salt, quaternary amine, stereochemically isomer, tautomer or N -oxide form.

A subject embodiment is the use of a compound of formula (la) or (lb) or any subgroup thereof as mentioned above as a useful embodiment for the manufacture of a medicament for the treatment of Gram-positive and / or Gram-negative bacterial infection.

A subject embodiment is the use of a compound of formula (la) or (lb) or any subgroup thereof as mentioned above as a useful embodiment for the manufacture of a medicament for the treatment of Gram-positive bacterial infection.

A subject embodiment is the use of a compound of formula (la) or (lb) or any subgroup thereof as mentioned above as a useful embodiment for the manufacture of a medicament for the treatment of Gram-negative bacterial infection.

Target embodiments IC ₉₀ against bacterial infections, at least one of the bacteria for the manufacture of a medicament for, in particular Gram-positive bacteria <15 ㎕ / ㎖, preferably a IC ₉₀ <10 ㎕ / ㎖, more preferably IC ₉₀ A useful embodiment with <5 μl / ml is the use of a compound of formula (la) or (lb) or any subgroup thereof: IC ₉₀ values are measured as described below.

Preferred compounds of the present invention are compounds 64, 8, 46, 12, 10, 24, 9, 13, 22, 33, 20, 65, 19, 59, 54, 26, 66, 67, 49 , 48, 70, 71, 21, 6, 45, 2, 5, 4, 1, 3, pharmaceutically acceptable acid or base addition salts, quaternary amines, stereochemical isomers, tautomers or N-oxide forms .

The invention also

And

And pharmaceutically acceptable acid or base addition salts, quaternary amines, stereochemical isomers, tautomers or N-oxide forms thereof.

In general, bacterial pathogens can be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds that are active against both Gram-positive and Gram-negative pathogens are generally considered to have a broad spectrum of activity. Compounds of the invention are considered to be active against Gram-positive and / or Gram-negative bacterial pathogens. In particular, the compounds of the invention are active against at least one Gram-positive bacteria, preferably against some Gram-positive bacteria, more preferably against one or more Gram-positive bacteria and / or one or more Gram-negative bacteria There is this. W ₁ is halo natan, the intermediate of formula (II) also exhibits antibacterial activity.

The compound of the present invention has bactericidal or bacteriostatic activity.

As examples of Gram-positive and Gram-negative aerobic and anaerobic bacteria, Staphylococci, such as S. aureus ; Enterocoxy, for example E. faecalis ; Streptococci, for example S. pneumoniae, S. mutans, S. pyogens ; Basilis, for example Bacillus subtilis ; Listeria, for example Listeria monocytogene s; Haemophilus, for example H. influenz a; Moraxella, for example M. catarrhalis ; Pseudomonas, for example Pseudomonas aeruginosa ; And Escherichia, for example E. coli . Gram-positive pathogens such as staphylococci, enterococci and streptococci, for example, are particularly important because they express resistant strains that are difficult to treat as well as difficult to eradicate from once established hospital environments. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium .

The compounds of the present invention also show activity against resistant bacterial strains.

The compounds of the invention are particularly active against Staphylococcus aureus and Streptococcus pneumoniae , including resistant Staphylococcus aureus , such as, for example, methicillin resistant Staphylococcus aureus (MRSA).

In particular, the compounds of the present invention are active against bacteria whose viability depends on the proper functionalization of F1F0 ATP synthase. Without being bound by theory, the activity of the compounds of the present invention depends on the inhibition of the F1F0 ATP synthase, in particular the inhibition of the F0 complex of the F1F0 ATP synthase, more specifically the inhibition of the subunit c of the F0 complex of the F1F0 ATP synthase. And depletion of the cellular ATP level of the bacteria induces the death of the bacteria.

Above and after, when a compound is used to treat bacteria, it means that the compound can always treat one or more bacterial strains.

When used above and after, a bacterial infection is not a mycobacterial infection, this means that the bacterial infection is not always infected with one or more mycobacterial strains.

The exact dosage and frequency of administration of the compounds of the present invention are well known to those skilled in the art, as well as other agents that can be ingested by the individual, as well as the particular compound of formula (Ia) or (Ib) used, the particular condition being treated, The severity of symptoms, age, weight, sex, diet, time of administration and general physical condition of the particular patient, and mode of administration. It is also clear that the effective daily amount may be lowered or increased depending on the response of the treated patient and / or the assessment of the clinician prescribing the compound of the invention.

The compounds of the present invention may optionally be administered in pharmaceutically acceptable form in a pharmaceutically acceptable carrier. The compound and the composition comprising the compound may be administered by a route such as local, local or systemic. Systemic applications include methods of introducing compounds into body tissues, such as intradural, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral administration. The specific dose of antibacterial agent to be administered outside the treatment period can be adjusted as needed.

Bacterial infections that can be treated by the compounds of the invention include, for example, central nervous system infection, ear canal infection, middle ear infection, such as acute otitis media, cranial sinuses infection, eye infection, oral infection, such as teeth, periodontal and Mucosal infections, Mutual respiratory tract infections, Respiratory tract infections, Urogenital infections, Gastrointestinal infections, Gynecologic infections, Sepsis, Bone and joint infections, Skin and skin structure infections, Bacterial endocarditis, Burns, Surgery, Antibacterial prevention and immunity Prevention of antibacterial in inhibitory patients, such as cancer chemotherapy patients or tracheal transplant patients.

Given the fact that the compounds of formula (la) or (lb) are active against bacteria, the compounds of the present invention may be combined with other antibacterial agents to effectively eliminate bacterial infections.

Therefore, the present invention also relates to a combination of compound (a) of formula (la) or (lb) and at least one other antibacterial agent (b), provided that at least one other antibacterial agent is not an antimycobacterial agent.

The invention also relates to a combination of compound (a) of formula (Ia) or (Ib) and at least one other antibacterial agent (b) for use as a medicament, provided that at least one other antibacterial agent is an antimycobacterial agent no.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (la) or (lb) as an active ingredient and at least one other antibacterial agent (b) that is not an antimycobacterial agent Also included in the present invention.

The invention also relates to the use of a combination or pharmaceutical composition as defined above for the treatment of a bacterial infection.

The pharmaceutical composition of the present invention may be formulated in various pharmaceutical forms for administration purposes. As suitable compositions, all compositions commonly used as systemic dosage agents can be cited. To prepare a pharmaceutical composition of the invention, an effective amount of a particular compound in the form of an addition salt, as an active ingredient, is optionally formulated in intimate mixture with a pharmaceutically acceptable carrier, wherein the carrier may vary depending on the form of preparation required for administration. Form). Such pharmaceutical compositions are particularly preferably a single dosage form suitable for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, in the case of oral liquid preparations such as suspending agents, syrups, elixirs, emulsions and solutions, any conventional pharmaceutical media such as water, glycols, oils, alcohols and the like may be used. Available; In the case of powders, pills, capsules, tablets and the like, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, and disintegrants may be used. Because of their ease of administration, tablets and capsules represent the most useful oral formulations, in which case solid pharmaceutical carriers are explicitly applied. In the case of parenteral compositions, the carrier generally comprises at least a large proportion in sterile water, although other components may be included, such as to aid dissolution. For example, an injectable solution may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.

Depending on the mode of administration, the pharmaceutical composition preferably comprises from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight of the active ingredient and from 1 to 99.95% by weight and more preferably from 30 to 99.9% by weight of a pharmaceutically acceptable carrier. And all percentages are based on the total composition.

When provided as a combination, the weight to weight ratio of the compound of formula (la) or (lb) and other antibacterial agent (b) can be determined by one skilled in the art. Such ratios, exact dosages, and frequency of administration are known to those skilled in the art, in addition to other agents that may be ingested by an individual, the compounds of formula (Ia) or (Ib) and other antibacterial agent (s) used, It depends on the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, general physical condition, and mode of administration of the particular patient. It is also evident that the daily effective amount may be lowered or increased depending on the response of the treated individual and / or the assessment of the clinician prescribing the compound of the invention.

The compounds of formula (la) or (lb) and one or more other antibacterial agents may be combined into a single formulation or they may be combined into separate formulations and administered simultaneously, separately or sequentially. Thus, the present invention also provides a product containing a compound of formula (la) or (lb) and at least one other antibacterial agent (b) as a combined formulation for simultaneous, separate or continuous use in the treatment of bacterial infections. And one or more other antibacterial agents are not antimycobacterial agents.

The pharmaceutical composition may further contain various other ingredients known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity-controlling agents, surfactants, preservatives, flavors or colorants.

The unit dosage form used in the present invention is particularly advantageous in formulating the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage forms are physically discrete units suited as single dosages, each unit comprising a predetermined amount of active ingredient calculated to provide the desired therapeutic effect in admixture with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scores or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, and their separate multiple batches. The daily dosage of the compound according to the invention may of course vary depending on the compound used, the mode of administration, the desired treatment and the bacterial disease indicated.

Other antibacterial agents that can be combined with compounds of formula (I) are antibacterial agents known in the art. Other antibacterial agents are β-lactam groups, such as natural penicillin, semisynthetic penicillin, natural cephalosporin, semisynthetic cephalosporin, cephamycin, 1-oxacefem, clavulanic acid, penem, carbapenem, nocardicin, monobactam Antibiotics; Tetracycline, anhydrotetracycline, anthracycline; Aminoglycosides; Nucleosides such as N -nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidine S; Macrolides such as 12-membered ring macrolide, 14-membered ring macrolide, 16-membered ring macrolide; Ansamycin; Bleomycin, Gramicidine, Polymyxin, Bacitracin, Cyclopeptide antibiotics containing lactone bonds, Actinomycin, Ampomycin, Capreomycin, Distamycin, Endurasidine, Micamycin, Neocardino Peptides such as statins, standomycin, biomycin, and viremiamycin; Cycloheximide; Ciacloserine; Bariotin; Sarcomycin A; Novobicin; Griseofulvin; Chloramphenicol; Mitomycin; Fumagillin; Monensin; Pyrronitrin; Fosfomycin; Pushic acid; D- ( p -hydroxyphenyl) glycine; D-phenylglycine; Contains enedine.

Certain antibiotics that may be combined with the compounds of formula (Ia) or (Ib) of the present invention are, for example, benzylphenicillin (potassium, procaine, benzartine), phenoxymethylphenicillin (potassium), pheneticillin potassium, propi Chillin, Carbenicillin (Disodium, Phenyl Sodium, Inmono Sodium), Sulbenicillin, Ticarcillin Disodium, Methicillin Sodium, Oxacillin Sodium, Cloxacillin Sodium, Dicloxacillin, Ploxacillin, Ampicillin , Mezzocillin, piperacillin sodium, amocillin, cyclacillin, hexillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, fibmesilin, cephalexin, cefachlor, cephaloglycine , Cephadroxyl, cepradine, ceproxadine, cefapirine sodium, cephalotin sodium, cephacetyl sodium, ceftulin sodium, cephaloridine, cephatrizin, cepharazone sodium, cephamandol, bepoti Cancer hydrochloride, Sephazoline Sodium, Ceftizone Sodium, Cytotaxime Sodium, Cefmenoxime Hydrochloride, Cefuroxime, Ceftriaxone Sodium, Ceftazidime, Sepoxitine, Cefmethazole, Cetathetan, Latamoxef, Clabulanic Acid, Imiphenem, Aztreonam, Tetracycline, Chlortetracycline Hydrochloride, Demethylchlortetracycline, Oxytetracycline, Metacycline, Doxycycline, Lolitetracycline, Minocycline, Daunorubicin Hydrochloride, Doxorubicin, Aklarubicin, Kanamycin Sulfate, becanamycin, tobramycin, gentamycin sulfate, dibecacin, amikacin, micronomycin, ribostamycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dehydrostreptomycin, destomycin A, hydromycin B, apramycin, sisomicin, Tylmycin Sulfate, Spectinomycin Hydrochloride, Astromycin Sulfate, Validamycin, Kasugamycin, Polyoxine, Blastisidine S, Erythromycin, Erythromycin Estoleate, Oleandomycin Phosphate, Tracetyloleandomycin, Kitasamycin, probemycin, spiramycin, tyrosine, ibemectin, midecamycin, bleomycin sulfate, pelopmycin sulfate, gramicidine S, polymyxin B, bacitracin, colistin sulfate, colistin methanesulfonate Sodium, Enlamycin, Mycamycin, Birginiamycin, Capreomycin Sulfate, Biomycin, Enbiomycin, Vancomycin, Actinomycin D, Neocaragenostatin, Vestatin, Pepstatin, Monensin, Lasaloside , Salinomycin, amphotericin B, nystatin, natamycin, trichomycin, mitramycin, lincomycin, clean Damycin, clindamycin palmitate hydrochloride, flabophospholifol, cycloserine, pessilosine, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrronitrine, phosphomycin, Fudicic acid, bicozamycin, thiamulin, cicanin.

Common manufacturing

The compounds according to the invention can generally be prepared in a series of steps, each known to those skilled in the art.

의 래디칼(여기에서, t 및 Z는 상기 정의된 바와 같음); 식

의 래디칼(여기에서, t 및 Z는 상기 정의된 바와 같음)에 의해 치환된 알킬옥시; 모노 또는 디(알킬)아미노(여기에서, 알킬은 알킬옥시 또는 Ar 또는 Het 또는 모르폴리닐 또는 2-옥소피롤리디닐중에서 각각 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환될 수 있음)[상기 R²는 R^2a로 나타내어짐]를 나타내는 화학식 (Ia)의 화합물[이 화합물은 화학식 (Ia-1)로 나타내어짐]은 W₁이 적합한 이탈기, 예를 들어 할로, 이를테면 클로로 등을 나타내는 화학식 (II)의 중간체를 임의로 적합한 용매, 예를 들어 알콜, 이를테면 메탄올 등, 아세토니트릴의 존재하, 및 임의로 적합한 염기, 예를 들어 KOH, 탄산이칼륨의 존재하에서 H-R^2a 또는 R^2a-H의 적합한 염 형태와 반응시킴으로써 제조할 수 있다.R ² is alkoxy; expression

Radicals, wherein t and Z are as defined above; expression

Alkyloxy substituted by radicals wherein t and Z are as defined above; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two substituents each independently selected from alkyloxy or Ar or Het or morpholinyl or 2-oxopyrrolidinyl] [ Wherein R ² is represented by R ^2a ], which compound is represented by formula (Ia-1), wherein W ₁ represents a suitable leaving group, for example halo, such as chloro, etc. The intermediate of formula (II) may be optionally substituted for HR ^2a or R ^2a -H in the presence of a suitable solvent such as alcohol, such as methanol, such as acetonitrile, and optionally in the presence of a suitable base such as KOH, dipotassium carbonate. It can be prepared by reacting with a suitable salt form.

R ² is Het or alkyl compound of formula (Ia) represents the [a R ² are indicated load by formula R ^2b] [This compound is represented by the formula (Ia-2) luggage] is the catalyst suitable for the intermediate of formula (II) For example Pd (PPh ₃ ) ₄ , suitable solvents such as dimethylether or alcohols such as methanol and the like, and R ^2b -B (OH) in the presence of suitable bases such as disodium carbonate or dipotassium carbonate It can manufacture by reacting with ₂ .

와 반응시킴으로써 제조할 수 있다.R ² is a compound of formula (Ia) containing a Het, for example, represents the pyridyl [The R ² is represented by Het luggage] [This compound is represented by the formula (Ia-3) Jim] is the intermediate of formula (II) In the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ , a suitable solvent such as dimethylether or an alcohol such as methanol and the like, and a suitable base such as disodium carbonate or dipotassium carbonate

It can manufacture by reacting with.

Compounds of formula (Ia) in which X is a direct bond, which intermediate is represented by formula (Ia-4), wherein W ₂ represents a suitable leaving group, for example halo, such as bromo, chloro, etc. Intermediates of are prepared in the presence of suitable coupling agents such as n-butyl lithium, sec-BuLi, in the presence of a suitable solvent such as tetrahydrofuran, and optionally of suitable bases such as 2,2,6,6 It can be prepared by reacting with an intermediate of formula (IV) in the presence of -tetramethylpiperidine, NH (CH ₂ CH ₂ CH ₃ ) ₂ , N, N-diisopropylamine or trimethylethylenediamine.

Compounds of formula (Ib) in which R ⁹ represents oxo can be prepared by reacting an intermediate of formula (II) with a suitable acid, for example HCl, in the presence of a suitable solvent, for example tetrahydrofuran.

A compound of formula (Ia) or (Ib), wherein X represents CH ₂ , which compound is represented by formula (Ia-5) or (Ib-I), represents a suitable couple of intermediates of formula (XX) or (XXI) Ring agents such as nBuLi, sec-BuLi, in the presence of a suitable solvent such as tetrahydrofuran, and optionally a suitable base such as 2,2,6,6-tetramethylpiperidine, NH (CH ₂ CH ₂ CH ₃ ) ₂ , N, N-diisopropylamine or trimethylethylenediamine in the presence of an intermediate of formula (IV).

In this reaction, the obtained compounds of formula (la) or (lb) can be separated and purified if necessary according to methods generally known in the art, for example extraction, crystallization, distillation, grinding and chromatography. . If a compound of formula (la) or (lb) precipitates, it can be separated by filtration. Alternatively, it can be crystallized by addition of a suitable solvent such as water, acetonitrile, alcohols such as methanol, ethanol and combinations of these solvents. In addition, the reaction mixture may be evaporated to dryness, and then the residue may be purified by chromatography (eg, reverse phase HPLC, flash chromatography, etc.). The reaction mixture may also be purified by chromatography without pre-evaporating the solvent. The compounds of formula (la) or (lb) can also be separated by evaporation of the solvent and then recrystallized from a suitable solvent such as water, acetonitrile, alcohols such as methanol and combinations of these solvents.

Those skilled in the art will recognize that which method should be used and which solvent is most suitable for use, and that this belongs to customary experiments to find the optimal separation method.

Compounds of formula (la) or (lb) can be further prepared by converting compounds of formula (la) or (lb) to other compounds of formula (la) or (lb) according to transformation reactions known in the art. .

Compounds of formula (la) or (lb) can be converted to the corresponding N -oxides according to methods known in the art for converting trivalent nitrogen to its N -oxide form. The N -oxidation reaction can generally be carried out by reacting the starting material of formula (la) or (lb) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; Suitable organic peroxides are, for example, benzenecarboperoxoacids or benzenecarboperoxoacids substituted with halo such as 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acid such as peroxoacetic acid, alkylhydroperoxides such as and peroxy acid, such as t-butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

과 반응시켜 R¹이 Het, 예를 들어 피리딘을 나타내는 화학식 (Ia)의 화합물[이 화합물은 화학식 (Ia-7)로 나타내어짐]로 전환시킬 수 있다.A compound of formula (Ia) in which R ¹ represents halo, which compound is represented by formula (Ia-6), is a suitable catalyst, for example Pd (PPh ₃ ) ₄ , a suitable solvent, for example dimethylether or alcohol In the presence of a suitable base such as disodium carbonate or potassium bicarbonate, for example methanol and the like.

Can be converted to a compound of formula (Ia) in which R ¹ represents Het, for example pyridine, which compound is represented by formula (Ia-7).

Compounds of formula (Ia-6) may also be formulated in which R ¹ represents methyl by reacting with Sn (CH ₃ ) _{4 in} the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ , a suitable solvent such as toluene ( Compounds of Ia), which are represented by the formula (Ia-8).

Some of the compounds of formula (Ia) or (Ib) and intermediates in the present invention may consist of a mixture of stereochemical isomers. Pure stereochemically isomeric forms of these compounds and intermediates can be obtained by applying techniques known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatography techniques such as countercurrent distribution, liquid chromatography, and the like. Enantiomers first convert the racemic mixture to a mixture of diastereomeric salts or compounds with a suitable dividing agent such as, for example, chiral acid; Physically separating this diastereomeric salt or mixture of compounds, for example, by methods such as selective crystallization or chromatography techniques such as liquid chromatography; Finally, this isolated diastereomeric salt or compound can be obtained from the racemic mixture by conversion to the corresponding enantiomer. Pure stereochemical isomers can also be obtained from pure stereochemical isomers of suitable intermediates and starting materials, provided that the intervening reaction occurs stereospecifically.

Separate ways of separating the enantiomeric forms of the compounds of formula (la) or (lb) and intermediates include liquid chromatography, in particular liquid chromatography using chiral stationary phases.

In the above or the following preparation method, it is understood that the reaction product can be separated from the reaction medium and purified if necessary according to methods generally known in the art such as, for example, extraction, crystallization, distillation, grinding and chromatography. Will be.

Some of the intermediates and starting materials are known compounds and are commercially available or can be prepared according to methods known in the art or according to the methods described in WO 2004/011436 or WO 2005/070430, which is incorporated herein by reference. have.

Intermediates of formula (II), wherein X is a direct bond, which intermediate is represented by formula (II-a), can be used to form intermediates of formula (V) in which W ₁ is defined above as a suitable coupling agent, for example nnBuLi, in the presence of sec-BuLi and a suitable solvent such as tetrahydrofuran, and a suitable base such as 2,2,6,6-tetramethylpiperidine, NH (CH ₂ CH ₂ CH ₃ ) ₂ , N, N It can be prepared by reacting with an intermediate of formula (IV) in the presence of diisopropylamine or trimethylethylenediamine.

Intermediates of formula (II), wherein X is CH ₂ , which intermediates are represented by formula (II-b), may be used to prepare intermediates of formula (VI) in the presence of a suitable coupling agent, for example nnBuLi, sec-BuLi, and Solvents such as tetrahydrofuran, and suitable bases such as 2,2,6,6-tetramethylpiperidine, NH (CH ₂ CH ₂ CH ₃ ) ₂ , N, N-diisopropylamine or trimethylethylene It can be prepared by reacting with an intermediate of formula (IV) in the presence of diamine.

R ¹ is an intermediate of formula (II) represents hydrogen - the intermediate is represented by the formula (II-c) Jim] is an intermediate of formula (V) R ¹ is halo [this intermediate is represented by the formula (Va) load; Can be prepared by reacting with an intermediate of formula (IV) in the presence of a suitable strong base such as nBuLi, sec-BuLi and in the presence of a suitable solvent such as tetrahydrofuran.

의 래디칼이며, 여기에서 s는 1의 정수이고, W₁은 클로로인 화학식 (V)의 중간체[이 중간체는 화학식 (V-b)로 나타내어짐]은 하기 반응식 (1)에 따라 제조될 수 있다:Intermediates of formula (V) are compounds that are commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, R ⁷ is hydrogen and R ⁶ is a formula

Is an radical of wherein s is an integer of 1 and W ₁ is chloro, which intermediate is represented by formula (Vb), which may be prepared according to the following scheme (1):

Scheme 1

In the above scheme,

All variables are as defined in formula (la).

Scheme 1 provides suitable substituted anilines with suitable acylchlorides such as 3-phenylpropionyl chloride, 3-fluorobenzenepropy in the presence of a suitable base such as triethylamine and a suitable reaction-inert solvent such as methylene chloride or ethylene dichloride. Reacting with onyl chloride or p-chlorobenzenepropionyl chloride (a). The reaction is conveniently carried out at temperatures ranging from room temperature to reflux temperature. In the next step (b), the adduct obtained in step (a) is reacted with phosphoryl chloride (POCl ₃ ) in the presence of a suitable solvent, for example N, N-dimethylformamide (Vilsmeier- Haack) after formylation, ring closure). The reaction is conveniently carried out at temperatures ranging from room temperature to reflux temperature. It will be appreciated that in the above or next preparation process, the reaction product may be separated from the reaction medium and, if necessary, purified according to methods generally known in the art such as, for example, extraction, crystallization and chromatography. In addition, it is clear that the reaction products present as one or more enantiomers can be separated from their mixtures by known techniques, in particular preparative chromatography, for example preparative HPLC. Typically, the compounds of formulas (la) and (lb) can be separated into their isomers.

Intermediates of formula (Va) wherein W ₁ represents chloro, which intermediates are represented by formula (Va-1), can be prepared by reacting the intermediate of formula (VII) with POCl ₃ .

Intermediates of formula (VII) may be prepared by reacting the intermediate of formula (VIII) with 4-methylbenzenesulfonyl chloride in the presence of a suitable solvent such as methylene chloride and a suitable base such as dipotassium carbonate.

Intermediates of formula (VIII) may be prepared by reacting the intermediate of formula (IX) with a suitable oxidizing agent such as 3-chlorobenzenecarboperoxoic acid in the presence of a suitable solvent such as methylene chloride.

Intermediates of formula (IX) wherein R ⁶ is hydrogen and R ⁷ is phenyl, which intermediates are represented by formula (IX-a), may be selected from suitable acids such as hydrochloric acid, iron chloride hexahydrate, It can be prepared by reaction with 3-chloro-1-phenyl-1-propanone in the presence of zinc chloride and a suitable solvent such as diethyl ether and a suitable alcohol such as ethanol.

의 래디칼이며, 여기에서 s는 1의 정수인 화학식 (IX)의 중간체[이 중간체는 화학식 (IX-b)로 나타내어짐]은 화학식 (XI)의 중간체를 디페닐 에테르의 존재하에서 반응시킴으로써 제조할 수 있다.R ⁷ is hydrogen and R ⁶ is

Is an radical of formula wherein s is an integer of 1, wherein the intermediate of formula (IX) is represented by formula (IX-b) can be prepared by reacting the intermediate of formula (XI) in the presence of diphenyl ether have.

Intermediates of formula (IX) may be prepared by reacting the intermediate of formula (XII) with the intermediate of formula (XIII) in the presence of a suitable base such as sodium hydroxide.

Intermediates of formula (IV) are compounds that are commercially available or can be prepared according to conventional reaction procedures generally known in the art. For example, an intermediate compound of formula (IV), wherein q is 1, which intermediate is represented by formula (IV-a), can be prepared according to the following scheme (2):

Scheme 2

Reaction Scheme 2 is suitable R ³ is a suitable Lewis acid, for example _{AlCl 3, FeCl 3, SnCl 4} , TiCl 4 or ZnCl ₂ and a suitable reaction-inert solvent, such as an appropriate acyl chloride in the presence of methylene chloride or ethylene dichloride, e.g. Step (a) is reacted by a Friedel-Craft reaction with 3-chloropropionyl chloride or 4-chlorobutyryl chloride. The reaction may conveniently be carried out at a temperature in the range from room temperature to reflux temperature. In the next step (b), an amino group (eg -NR ⁴ R ⁵ ) is introduced by reacting the intermediate compound obtained in step (a) with the appropriate amine HNR ⁴ R ⁵ .

Intermediates of formula (IV-a) also contain intermediates of formula (XIV) with HC (═O) H and suitable in the presence of suitable solvents such as alcohols such as methanol, ethanol and the like, and suitable acids such as hydrochloric acid. It can be prepared by reacting with the amino group HNR ⁴ R ⁵ , for example NH (CH ₃ ) ₂ .HCl.

Intermediate of formula (VI), wherein W ₁ represents chloro, which intermediate is represented by formula (VI-a), represents an intermediate of formula (XV) with benzyltriethylammonium chloride (phase transfer agent) and a suitable solvent, for example It can be prepared by reacting with POCl _{3 in} the presence of acetonitrile.

의 래디칼이며, 여기에서 s는 1의 정수인 화학식 (XV)의 중간체[이 중간체는 화학식 (XV-a)로 나타내어짐]은 화학식 (XVI)의 중간체를 적합한 염기, 예를 들어 수산화칼륨 및 적합한 용매, 예를 들어 1,2-에탄디올의 존재하에서 NH₂-NH₂와 반응시킴으로써 제조할 수 있다.R ⁶ is

Is an radical of formula (XV) wherein s is an integer of 1, wherein the intermediate is represented by formula (XV-a), and the intermediate of formula (XVI) is a suitable base such as potassium hydroxide and a suitable solvent. For example, by reacting with NH ₂ -NH _{2 in} the presence of 1,2-ethanediol.

는 1-(2-아미노페닐)에타논과 β-옥소벤젠프로판산 에틸 에스테르를 반응시킴으로써 제조할 수 있다.Is an intermediate of formula (XVI)

Can be prepared by reacting 1- (2-aminophenyl) ethanone with β-oxobenzenepropanoic acid ethyl ester.

Intermediates of formula (III), wherein R ² represents C _1-6 alkyloxy, which intermediates are represented by formula (III-a), may be selected from intermediates of formula (XVII) in a suitable solvent, for example corresponding C _1- It can be prepared by reacting with a suitable C _1-6 alkylO- salt in the presence of _{6 alkylOH} .

Intermediates of formula (XVII) may be prepared by reacting intermediates of formula (XVIII) with POCl ₃ .

의 래디칼이며, 여기에서 s는 0의 정수인 화학식 (XVIII)의 중간체[이 중간체는 화학식 (XVIII)-a)로 나타내어짐]은 화학식 (XIX)의 중간체를 AlCl₃ 및 적합한 용매, 예를 들어 클로로벤젠의 존재하에서 폐환시킴으로써 제조할 수 있다.R ⁷ is hydrogen, R ⁶ is a formula

Is an radical of formula (XVIII), wherein s is an integer of 0, which intermediate is represented by formula (XVIII) -a), wherein the intermediate of formula (XIX) is selected from AlCl ₃ and a suitable solvent such as chloro It may be produced by ring closing in the presence of benzene.

로 나타내어진다.In the intermediate of formula (III), the R ¹ substituent may represent halo, which can then replace the W ₂ leaving group. Such intermediates of formula (III)

It is represented by

Intermediates of formula (XX), wherein R ² is C _1-6 alkyloxy, which intermediates are represented by formula (XX-a) represent intermediates of formula (VI-a) with suitable alcohols, such as C _1-6 alkylOH from it can be prepared by C _1-6 alkyloxy Na and reaction.

Hereinafter, the present invention will be described by way of example and without limitation.

Experimental part

The absolute stereochemical configuration of the stereo carbon atom (s) in some compounds has not been determined experimentally. In this case, the first separated stereochemical isomer was designated as "A" and the second separated was designated as "B" without considering the actual stereochemical form anymore. However, the "A" and "B" isomers can be clearly specified by those skilled in the art using known methods such as X-ray diffraction. The separation method is described in detail below.

In synthesizing the compounds of the present invention, reference is made to WO 2005/070430, which is incorporated herein by reference.

Then, 'MP' means melting point, 'DIPE' means diisopropyl ether, 'DMF' means N, N- dimethylformamide, 'THF' means tetrahydrofuran, ' EtOAc 'means ethyl acetate and' DCM 'means dichloromethane.

A. Preparation of Intermediates

Example A1

Preparation of Intermediate 1

Benzenepropanoyl chloride (0.488 mol) was added dropwise to a solution of 4-bromo benzeneamine (0.407 mol) in Et ₃ N (70 ml) and DCM (700 ml) at room temperature and the mixture was stirred at room temperature overnight. The mixture was poured into water and concentrated NH ₄ OH and extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and the solvent evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in DCM and washed with 1N HCl. The organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated to yield 107.67 g of intermediate 1 (87%).

Example A2

Preparation of Intermediate 2

Phosphorus trichloride (1.225 mol) was added dropwise to DMF (0.525 mol) at 10 ° C. Intermediate 1 (0.175 mol) was then added at room temperature. The mixture was stirred at 80 ° C. overnight, poured onto ice and extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and the solvent evaporated. The product was used without further purification to yield 77.62 g of intermediate 2 (67%).

Example A3

a) Preparation of Intermediate 3

A mixture of intermediate 2 (0.233 mol) in MeOH (776 ml) and 30% MeONa solution in MeOH (222.32 ml) was stirred at reflux overnight, poured into ice and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM / cyclohexane 20/80 followed by 100/0; 20-45 μm). Pure fractions were combined and the solvent was evaporated to yield 25 g of intermediate 3 (33%).

The following intermediates were obtained according to the method described above.

b) preparation of intermediate 4

A mixture of EtOH (150 ml) and Intermediate 2 (0.045 mol) in 21% EtONa solution (50 ml) in EtOH was stirred at reflux for 12 hours. The mixture was poured on ice and extracted with DCM. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated to give 15.2 g of intermediate 4 (98%).

Example A4

a) Preparation of Intermediate 5

Aluminum chloride (1.31 mol) was added to a mixture of N- (3-bromophenyl) -α- (phenylmethylene) benzeneacetamide (0.1311 mol) in chlorobenzene (500 ml) at room temperature. The mixture was stirred at reflux for 3 hours, then cooled to room temperature, poured into ice water and filtered. The filtrate was washed with H ₂ O followed by cyclohexane and then dried to give 35.5 g of intermediate 5 (95%).

b) preparation of intermediate 6 and intermediate 7

A mixture of intermediate 5 (0.2815 mol) in phosphorus trichloride (320 ml) was stirred at reflux for 1 hour, then cooled to room temperature and the solvent was evaporated to dryness. The residue was taken up in H ₂ O. The mixture was extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated to dryness. The residue (58.2 g) was purified by column chromatography on silica gel (eluent: toluene / cyclohexane 80/20; 15-35 μm). The two fractions were combined and the solvent was evaporated to give 21 g of intermediate 6 and 34.5 g of intermediate 7.

c) preparation of intermediate 8

A mixture of MeOH (300 ml) and Intermediate 6 (0.0659 mol) in 3% MeONa solution (0.329 mol) in MeOH was stirred under reflux for two days, then cooled to room temperature, poured into ice water and filtered. The filtrate was washed with H ₂ O and dried to give 19 g of intermediate 8 (92%).

Example A5

a) Preparation of Intermediate 9

A mixture of 5-bromo-1H-indole-2,3-dione (0.28 mol) in 3N NaOH (650 ml) was stirred and heated at 80 ° C. for 30 minutes and then cooled to room temperature. Benzenepropanal (0.28 mol) was added and the mixture was stirred to reflux overnight. The mixture was cooled to room temperature and acidified to pH 5 with HOAc. The precipitate was filtered off, washed with H ₂ O and dried (vacuum) to yield 50 g of intermediate 9 (52%).

b) preparation of intermediate 10

A mixture of intermediate 9 (0.035 mol) in 1,1′-oxybisbenzene (100 ml) was stirred and heated at 300 ° C. for 8 hours and then cooled to room temperature. This process was repeated four times. The four mixtures were combined and purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 followed by 99/1). Pure fractions were combined and the solvent was evaporated to give 25.6 g of intermediate 10 (61%).

Example A6

a) Preparation of Intermediate 11

HCl / diethyl ether (30 ml) was added to a solution of 4-bromobenzeneamine (0.139 mol) in EtOH (250 ml) and the mixture was stirred for 30 minutes. Iron chloride hexahydrate (0.237 mol) followed by zinc chloride (0.014 mol) was added and the mixture was stirred at 80 ° C. for 30 minutes. 3-chloro-1-phenyl-1-propanone (0.146 mol) was added and the mixture was stirred at 80 ° C overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, then washed with 10% K ₂ CO ₃ , dried (MgSO ₄ ), filtered and evaporated. The residue (25 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH 100/0 followed by 97/3) (35-70 μm). Pure fractions were combined and evaporated to give 17.5 g of intermediate 11 (44%).

b) preparation of intermediate 12

3-Chlorobenzenecarboperoxoic acid (0.12 mol) was added portionwise to a solution of intermediate 11 (0.0598 mol) in DCM (200 ml) at room temperature and the mixture was stirred at room temperature overnight. 10% K ₂ CO ₃ was added and the organic layer was decanted and dried (MgSO ₄ ), after filtration, the volume of intermediate 12 was evaporated to 150 ml.

c) preparation of intermediate 13

4-Methylbenzenesulfonyl chloride (0.075 mol) is added in portions to a solution of intermediate 12 (0.0598 mol) in DCM (150 ml) and 10% K ₂ CO ₃ solution (150 ml) at room temperature, and the mixture is stirred overnight at room temperature. It was. Diethyl ether was added and filtered. The precipitate was washed with diethyl ether and evaporated to dryness to afford 14 g of intermediate 13 (78%).

d) preparation of intermediate 14

A mixture of intermediate 13 (0.047 mol) in phosphorus trichloride (150 ml) was stirred at reflux for 48 hours. The mixture was evaporated and the residue was taken up in NH ₄ OH and then extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and evaporated to afford 13 g of intermediate 14 (87%).

Example A7

a) Preparation of Intermediate 15

A mixture of 1- (2-aminophenyl) ethanone (0.37 mol) and β-oxobenzenepropanoic acid ethyl ester (1.48 mol) was stirred overnight at 180 ° C. The mixture was brought to room temperature. The precipitate was filtered off, washed with diethyl ether and dried. The residue was crystallized with DIPE. The precipitate was filtered off and dried to give 56.6 g of intermediate 15 (58%).

b) preparation of intermediate 16

A mixture of intermediate 15 (0.076 mol) and hydrazine (0.76 mol) in 1,2-ethanediol (240 ml) was stirred at 100 ° C for 1 hour. KOH (0.266 mol) was added. The mixture was stirred at 180 ° C overnight. H ₂ O was added. The mixture was acidified and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (12.05 g) was crystallized with DIPE. The precipitate was filtered off and dried to yield 4.74 g of intermediate 16.

c) preparation of intermediate 17

Phosphorus trichloride (0.057 mol) was added slowly at 80 ° C. to a mixture of intermediate 16 (0.019 mol) and benzyltriethylammonium chloride (0.0532 mol) in acetonitrile (50 ml). The mixture was stirred overnight. The solvent was evaporated. The mixture was poured into ice and 10% Na ₂ CO ₃ and extracted with DCM. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated to yield 4.08 g of intermediate 17.

d) preparation of intermediate 17a

A mixture of intermediate 17 (0.0153 mol) and sodium methoxide (30 wt% solution in MeOH, 7 ml) in MeOH (35 ml) was stirred at 80 ° C. for 24 h. Water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was crystallized with diisopropyl ether. The precipitate was filtered off and dried. Yield: 2.77 g of intermediate 17a (69%).

Example A8

a) Preparation of Intermediate 18 and Intermediate 19

A mixture of aluminum chloride (0.257 mol) and 3-chloropropanoyl chloride (0.234 mol) in 1,2-dichloroethane (100 ml) was stirred at 0 ° C. A solution of naphthalene (0.234 mol) in 1,2-dichloroethane (100 ml) was added. The mixture was stirred at 0 ° C. for 1 h and then poured into ice water. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (56 g) was purified by column chromatography on silica gel (eluent: cyclohexane / DCM 60/40; 20-45 μm). The two fractions were combined and the solvent was evaporated to yield two fractions of 31 g of fraction 1 and 14 g of fraction 2 as intermediate 18 (61%). Fraction 2 was taken up in DIPE and the precipitate obtained was then filtered off and dried to give 8.2 g of intermediate 19.

b) preparation of intermediate 20

A mixture of intermediate 18 (0.0137 mol), N-methylbenzenemethanamine (0.015 mol) and K ₂ CO ₃ (2 g) in acetonitrile (100 ml) was stirred at 80 ° C. for 2 hours. H ₂ O was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated to yield 4.2 g of intermediate 20 (100%).

Example A9

Preparation of Intermediate 21

N-methylmethanamine hydrochloride (0.052 mol), formaldehyde (0.05 mol) and 1- (3,5-difluorophenyl) ethanone (0.013 mol) in concentrated HCl (0.1 ml) in EtOH (20 ml) The mixture of was stirred at 80 ° C. for 20 hours and then cooled to room temperature. The solvent was evaporated to dryness. The residue was taken up in 3N HCl. The mixture was washed with diethyl ether, basified with K ₂ CO ₃ and then extracted with diethyl ether. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated to yield 2 g of intermediate 21.

Example A10

a) Preparation of Intermediate 22 and Intermediate 23

1.6M butyllithium (0.12 mol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (0.12 mol) in THF (200 ml) under N ₂ flow at -10 ° C. The mixture was stirred at -10 ° C for 20 minutes and then cooled to -70 ° C. A mixture of intermediate 2 (0.1 mol) in THF (100 ml) was added. The mixture was stirred at -70 ° C for 45 minutes. A solution of 3- (dimethylamino) -1-phenyl-1-propanone (0.1 mol) in THF (100 ml) was added. The mixture was stirred at -70 ° C for 1 hour, reached -50 ° C and then hydrolyzed. H ₂ O (100 ml) was added at -50 ° C. The mixture was stirred at rt for 30 min and extracted with EtOAc. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was taken up in EtOAc. The precipitate was filtered off, washed with EtOAc and diethyl ether and dried in vacuo to give 4 g of intermediate 23 (8%). The mother layer was evaporated. The residue (26 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 97/3 / 0.1; 15-40 μm). The desired fractions were combined and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to give 1 g of intermediate 22.

The following intermediates were prepared according to the method described above.

b) preparation of intermediate 24

1.6M butyllithium (0.0094 mol) was added dropwise to a mixture of 2,2,6,6-tetramethylpiperidine (0.0094 mol) in THF (20 ml) under N ₂ flow at -20 ° C. The mixture was stirred at -20 ° C for 20 minutes and then cooled to -70 ° C. A solution of 6-bromo-2-chloro-3-phenylquinoline (0.0062 mol) in THF (40 ml) was added. The mixture was stirred at -70 ° C for 1 hour. A solution of intermediate 21 (0.0094 mol) in THF (25 ml) was added. The mixture was stirred at −70 ° C. to room temperature for 18 hours. H ₂ O and EtOAc were added. The organic layer was washed with saturated NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (4.3 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 97/3 / 0.1; 1 Oμm). Pure fractions were combined and the solvent was evaporated to yield 0.77 g of intermediate 24 (23%).

The following intermediates were prepared according to the method described above.

c) preparation of intermediate 28

1.6 M butyllithium (0.029 mol) was added to a solution of N-propyl-1-propanamine (0.029 mol) in THF (50 ml) under N ₂ flow at −10 ° C. The mixture was stirred for 20 minutes and then cooled to -70 ° C. A solution of intermediate 2 (0.024 mol) in THF (30 ml) was added. The mixture was stirred at -70 ° C for 1 hour. A solution of 3- (dimethylamino) -1- (2-thienyl) -1-propanone (0.029 mol) in THF (20 ml) was added. The mixture was stirred at -70 ° C for 1 hour, then reached -20 ° C and extracted with EtOAc. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 96/4 / 0.1; 20-45 μm). Pure fractions were combined and the solvent was evaporated. The residue (4.65 g) was crystallized with DIPE. The precipitate was filtered off and dried to yield 2.7 g of intermediate 28 (MP: 168 ° C). The mother layer was further evaporated to give 1.7 g of intermediate 28.

d) preparation of intermediate 25

1.6M butyllithium (0.0112 mol) was added to a solution of N- (1-methylethyl) -2-propanamine (0.0112 mol) in THF (20 ml) under N ₂ flow at -20 ° C. The mixture was stirred at -20 ° C for 30 minutes and then cooled to -70 ° C. A solution of intermediate 17 (0.0094 mol) in THF (20 ml) was added. The mixture was stirred for 45 minutes. A solution of intermediate 21 (0.0112 mol) in THF (10 ml) was added. The mixture was stirred at −70 ° C. for 2 hours, then poured into H ₂ O at −30 ° C. and extracted with EtOAc. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (4 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH 98: 2; 15-40 μm). Pure fractions were combined and the solvent was evaporated. The residue (3 g) was crystallized with DIPE. The precipitate was filtered off and dried to yield 1.94 g of intermediate 25 (MP: 140 ° C).

e) preparation of intermediate 26

1.6M butyllithium (0.013 mol) was added to a solution of N- (1-methylethyl) -2-propanamine (0.013 mol) in THF (20 ml) under N ₂ flow at -30 ° C. The mixture was stirred at -20 ° C for 30 minutes and then cooled to -70 ° C. A solution of 2-chloro-4-methyl-3-phenylquinoline (0.011 mol) in THF (20 ml) was added. The mixture was stirred for 45 minutes. A solution of intermediate 21 (0.013 mol) in THF (10 ml) was added. The mixture was stirred at -70 ° C for 2 h, then poured into H ₂ O and extracted with EtOAc. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (5 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH 98: 2; 15-40 μm). Pure fractions were combined and the solvent was evaporated to give 4 g of intermediate 26 (78%).

f) preparation of intermediate 27

1.6M butyllithium (0.0075 mol) in hexane was added dropwise to a mixture of intermediate 14 (0.0062 mol) in THF (20 ml) under N ₂ flow at −70 ° C. The mixture was stirred at -70 ° C for 1 hour. A solution of intermediate 21 (0.0075 mol) in THF (10 ml) was added at -70 ° C. The mixture was stirred at −70 ° C. to room temperature and then stirred for 18 hours. H ₂ O was added. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (3 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 97/3 / 0.1; 1 Oμm). Pure fractions were combined and the solvent was evaporated to yield 1.1 g of intermediate 27 (39%).

The following intermediates were prepared according to the method described above.

B. Preparation of Final Compound

Example B1

a) Preparation of Compound 1

1.6M butyllithium (0.0019 mol) was added dropwise to a mixture of intermediate 8 (0.0016 mol) in THF (5 ml) under N ₂ flow at −70 ° C. The mixture was stirred at -70 ° C for 1 hour. A solution of intermediate 21 (0.0019 mol) in THF (2 ml) was added. H ₂ O was added. The mixture was extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 98/2 / 0.1; 10 μm). Pure fractions were combined and the solvent was evaporated to yield 0.2 g of compound 1 (28%, MH &lt; + &gt;: 449).

The following final compounds were prepared according to the method described above.

b) Preparation of Compound 7

Butyllithium (0.0035 mol) was added dropwise to a mixture of N- (1-methylethyl) -2-propanamine (0.0034 mol) in THF (10 ml) under N ₂ flow at -20 ° C. The mixture was stirred at -20 ° C for 20 minutes and then cooled to -70 ° C. A solution of intermediate (0.0029 mol) in THF (10 ml) was added. The mixture was stirred at -70 ° C for 2 h. A solution of intermediate 21 (0.0032 mol) in THF (10 ml) was added at -70 ° C. The mixture was stirred at −70 ° C. for 3 hours, poured into ice water and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (1.4 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 99/1 / 0.1; 15-40 μm). The desired fractions were combined and the solvent was evaporated. The residue (0.968 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 98/2 / 0.2; 15-40 μm). Pure fractions were combined and the solvent was evaporated. The residue was dried to give 0.151 g of compound 7 (11%, oil, check structure by NMR).

Example B2

a) Preparation of Compound 8

30% MeONa solution (2 ml) was added to a mixture of intermediate 23 (0.002 mol) in MeOH (2 ml) at room temperature. The mixture was stirred at reflux overnight, poured into ice and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (0.62 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 95/5 / 0.5; 15-40 μm). Pure fractions were combined and the solvent was evaporated. The obtained residue (0.39 g) was crystallized with DIPE. The precipitate was filtered off and dried to yield 0.15 g of compound 8 (MP: 66 ° C).

The following final compounds were prepared according to the method described above.

b) Preparation of Compound 17

A mixture of intermediate 25 (0.0004 mol) and pyrrolidine (0.0021 mol) was stirred at 90 ° C. overnight, poured into H ₂ O and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (0.18 g) was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 98/2 / 0.1; lOμm). The desired fractions were combined and the solvent was evaporated to afford 0.043 g of compound 17 (20%, MH <+>: 516).

The following final compounds were prepared according to the method described above.

c) preparation of compound 21

A mixture of intermediate 26 (0.0006 mol), phenyl boronic acid (0.0019 mol), Pd (PPh ₃ ) ₄ (0.00006 mol) and Na ₂ CO ₃ (0.0032 mol) in dimethyl ether (10 ml) was stirred overnight at 90 ° C. , Poured into H ₂ O, and extracted with CH ₂ Cl ₂ . The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (0.48 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 99/1; lOμm). Pure fractions were combined and the solvent was evaporated. Yield: 0.054 g of compound 21 (16%, MP: 173 ° C).

d) preparation of compound 22

A mixture of intermediate 24 (0.0003 mol), imidazole (0.0018 mol) and K ₂ CO ₃ (0.0011 mol) in acetonitrile (10 ml) was stirred under reflux for 48 hours and then cooled to room temperature. H ₂ O was added. The mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.23 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 97/3 / 0.1). Pure fractions were combined and the solvent was evaporated. Yield: 0.09 g of compound 22 (42%) (melting point: 136 ° C).

The following final compounds were prepared according to the method described above.

e) preparation of compound 42

Intermediate 27 (0.0005 mol) in 3-dimethyl ether (7 ml) and MeOH (3 ml), 3- (1,3,2-dioxaborgan-2-yl) pyridine (0.0008 mol), tetrakis (triphenylforce) Pin) palladium (0.0005 mol) and a mixture of 2M K ₂ CO ₃ solution (0.0027 mol) was stirred at 100 ° C. under N ₂ flow for 18 hours and then cooled to room temperature. H ₂ O was added. The mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.34 g) was taken up in 2-propanone (6 ml). Oxalic acid was added. The mixture was stirred. The precipitate was filtered off and dried under vacuum at 60 ° C. to give 0.29 g of compound 42 as the ethanedioic acid salt (1: 2) (80%, MP: 151 ° C.).

The following final compounds were prepared according to the method described above.

f) preparation of compound 45

A mixture of intermediate 37 (0.0007 mol) in N-methylmethanamine (10 ml) and acetonitrile (10 ml) was stirred at 90 ° C. for 12 hours, then poured into H ₂ O / K ₂ CO ₃ and extracted with DCM It was. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The resulting fractions (0.25 g) were stirred at 90 ° C. for 72 h and purified by column chromatography on chromasil (eluent: DCM / MeOH 99/1; 10 μm). The desired product fractions were combined and the solvent was evaporated. The residue (0.08 g) was dissolved in oxalic acid / 2-propanol and converted to ethanedioic acid salt (1: 2.5). The precipitate was filtered off and dried to afford 0.07 g of compound 45 (14%, MP: 136 ° C.).

The following final compounds were prepared according to the method described above.

g) Preparation of Compound 48

A mixture of KOH (0.0011 mol) in 1-piperidineethanol (2 ml) was stirred at 80 ° C. until KOH disappeared. Intermediate 23 (0.0009 mol) was added. The mixture was stirred at 80 ° C. overnight, then poured onto ice and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue (2.49 g) was crystallized with DIPE. The precipitate was filtered off and dried to yield 0.308 g of compound 48 (MP: 131 ° C).

The following final compounds were prepared according to the method described above.

h) Preparation of Compound 50

A mixture of intermediate 23 (0.000137 mol), N-methylmethanamine (0.000412 mol, 3 equiv) and K ₂ CO ₃ (3 equiv) in acetonitrile (2 ml) was stirred at 80 ° C. for 12 h and then H ₂ Poured into O and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The resulting fractions were purified by column chromatography on silica gel, then the desired product fractions were collected and the solvent was evaporated to afford 0.07 g of compound 50 (54.79%, MH <+>: 518).

The following final compounds were prepared according to the method described above.

Example B3

a) Preparation of Compound 64

Compound 9 (0.0003 mol), 3- (1,3,2-dioxaborinan-2-yl) pyridine (0.0006 mol) in dimethyl ether (6 ml) and MeOH (2 ml), tetrakis (triphenylforce) Pin) palladium (0.00003 mol) and a mixture of 2M K ₂ CO ₃ solution (0.0015 mol) were stirred at 100 ° C. for 18 hours under N ₂ flow and then cooled to room temperature. H ₂ O was added. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.14 g) was taken up in 2-propanone (2 ml). Oxalic acid (2 equiv) was added. The mixture was stirred for 10 minutes. The precipitate was filtered off, washed with 2-propanone and dried under vacuum at 70 ° C. to afford 0.077 g of compound 64 as the ethanedioic acid salt (1: 1.5) (38%, MP: 156 ° C.).

The following final compounds were prepared according to the method described above.

b) Preparation of Compound 66

Compound 8 (0.0003 mol), tetrakis (triphenylphosphine) palladium (0.00003 mol), 2M Na ₂ CO ₃ solution (0.0019 mol) and 3- (1,3,2-dioxa in dimethyl ether (6 ml) A mixture of boranan-2-yl) pyridine (0.0011 mol) was stirred at 100 ° C. overnight, then poured into H ₂ O and extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue was purified by column chromatography on chromasil (eluent: toluene / 2-propanol / NH ₄ OH 80/20/1; 10 μm). Pure fractions were combined and the solvent was evaporated. The residue (0.1 g, 51%) was crystallized with DIPE / acetonitrile. The precipitate was filtered off and then dried to yield 0.057 g of compound 66 (MP: 180 ° C.).

The following final compounds were prepared according to the method described above.

c) preparation of compound 68

A mixture of compound 10 (0.0007 mol), tetrakis (triphenylphosphine) palladium (0.00007 mol) and tetramethylstanan (0.0016 mol) in toluene (6 ml) was stirred at reflux overnight. H ₂ O was added. The mixture was extracted with DCM. The organic layer was separated and dried (MgSO ₄ ), filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH / NH ₄ OH 95/5 / 0.3; 20 μm). Pure fractions were combined and the solvent was evaporated to afford 0.038 g of compound 68 (11%, MH <+>: 447).

Example B4

Preparation of Compound 69

A mixture of intermediate 32 (0.0016 mol) in 6N HCl (5 ml) and THF (10 ml) was stirred at 80 ° C. for 48 hours, then cooled to room temperature and poured into a 10% K ₂ CO ₃ solution and extracted with EtOAc. . The organic layer was washed with saturated NaCl, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was crystallized from diethyl ether / 2-propanone. The precipitate was filtered off and dried. A portion of this fraction (0.3 g (44%) in 0.6 g) was taken up in hot 2-propanone. The precipitate was filtered off and dried to yield 0.2 g of compound 69 (15%, MP: 190 ° C.).

Example B5

a) Preparation of Compound 70

n-butyl lithium (0.0022 mol) was added slowly to a mixture of diisopropyl amine (0.0022 mol) in THF (10 ml) at -20 ° C. under N ₂ . The mixture was stirred for 20 minutes and then cooled to -70 ° C. A solution of intermediate 17a (0.0019 mol) in THF (10 ml) was added. The mixture was stirred for 1 hour. A solution of 3- (dimethylamino) -1- (1-naphthalenyl) -1-propanone (0.0028 mol) in THF (10 ml) was added at -70 ° C. The mixture was stirred for 1 hour. H ₂ O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (1.13 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / iPrOH / NH ₄ OH 96/4 / 0.2; 15-40 μm). Pure fractions were combined and the solvent was evaporated. Yield: 0.04 g of Compound 70 (4%; MH <+>: 491).

b) Preparation of Compound 71

The compound was prepared according to B5a).

The residue (1 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / MeOH / NH ₄ OH 99/1 / 0.1; 15-40 μm). Pure fractions were combined and the solvent was evaporated. The residue (0.32 g, 37%) was crystallized from diisopropyl ether. The precipitate was filtered off and dried. Yield: 0.133 g of Compound 71 (15%, Melting Point: 123 ° C).

C. Analysis Method

Compound mass was recorded by LCMS (Liquid Chromatography Mass Spectroscopy). Three methods are described below. The data is summarized in Table 1 below.

LCMS-Method 1:

LCMS analysis was performed on a Chromasil C18 column (Interchim, Montlucon, FR; 5 μm, 4.6 × 150 mm) at a flow rate of 1 ml / min (electrospray ionization in positive mode, 100-900 amu scanning mode). 100% A with 2 mobile phases (mobile phase A: 30% 6.5 mM ammonium acetate + 40% acetonitrile + 30% formic acid (2 ml / l); mobile phase B: 100% acetonitrile) 100% in 4 minutes from 1 minute With B, 100% B was loaded in a gradient condition of 100% A minutes within 3 minutes from 5 minutes and re-equilibrated with 100% A for 2 minutes.

LCMS-Method 2:

LCMS analysis was performed on a Chromasil C18 column (Interchim, Montlucon, FR; 3.5 μm, 4.6 × 100 mm) with a flow rate of 0.8 ml / min (electrospray ionization in positive and negative (pulsation) mode). 100% A as two mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml / l); mobile phase B: 100% acetonitrile) 100% in 4 minutes from 1 minute B, 100% B, loaded at a gradient of 100% A at 0.8 ml / min in 3 minutes from 4 minutes at 1.2 ml / min flow rate and re-equilibrated at 100% A for 1.5 minutes.

LCMS-Method 3:

LCMS analysis was performed on an Xterra MS C18 column (Waters, Millford USA; 5 μm, 4.6 × 150 mm) with a flow rate of 1 ml / min (electrospray ionization in positive mode, 100-1000 amu scanning mode). Two mobile phases (mobile phase A: 85% 6.5 mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) as 100% A in 100 minutes B, 100 in 5 minutes from 3 minutes As a% B, it was loaded at a gradient of 100% A at 0.8 ml / min within 3 minutes from 6 minutes at a flow rate of 1.2 ml / min and re-equilibrated at 100% A for 3 minutes.

Table 1 :

Analysis method used

D. Pharmacological Examples

Preparation of Bacterial Suspensions for Susceptibility Testing:

The bacteria used in this study were grown overnight with stirring at 37 ° C. in a flask containing 100 ml Mueller-Hinton broth (Becton Dickinson-catalog No. 275730) in sterile deionized water. Stock (0.5 mL / tube) was stored at −70 ° C. until use. Bacterial titer measurements were performed on microtiter plates and colony forming units (CFUs) were determined. In general, an inoculum level of approximately 100 CFU was used for the sensitivity test.

Antibacterial Susceptibility Test: IC ₉₀  Measure

Microtiter Plate Analysis

Sterile 96-well plastic microtiter plates were filled with 180 μl of sterile deionized water supplemented with 0.25% BSA. A stock solution of the compound (7.8 × final test concentration) was then added to column 2 in 45 μl volume. Serial 5-fold dilutions (45 μl in 180 μl) were prepared directly on microtiter plates from column 2 to column 11. An untreated control sample (column 1) containing an inoculum and an untreated control sample (column 12) without it were included in each microtiter plate. Depending on the type of bacteria, about 10-60 CFU / well of bacterial inoculum (100 TCID50) was added to columns A-H except column 12 in a volume of 100 μl in 2.8 × Müller-Hinton broth medium. Equal amounts of broth medium without inoculum were added to columns 12 in columns A through H. Cultures were incubated at 37 ° C. for 24 hours in normal atmosphere (incubator with open air valve and continuously ventilated). After incubation and one day after inoculation, bacterial growth was measured by immunofluorescence. Thus, 3 hours after inoculation, resazurin (0.6 mg / ml) was added to all wells at a dose of 20 μl and the microtiter plate was reincubated overnight. There was bacterial growth as the color changed from blue to pink. Fluorescence was read at an excitation wavelength of 530 nm and emission wavelength of 590 nm on a computer-controlled fluorometer (Cytofluor Biosearch). The percent inhibition of growth achieved by the compound was calculated according to standard methods. IC ₉₀ (expressed in μg / ml) is defined as the 90% inhibitory concentration on bacterial growth. The results are shown in Table 2 below.

Agar dilution method

MIC ₉₉ levels (minimum concentrations to achieve 99% inhibition of bacterial growth) can be measured by performing standard agar dilution methods according to the NCCLS standard ^* , wherein the medium used comprises Müller-Hinton agar.

^* Clinical laboratory strandard institute. 2005. Methods for dilution Antimicrobial susceptibility tests for bacteria that grows Aerobically; Revised Standard-Sixth Edition.

Time kill assays

The bactericidal or bacteriostatic activity of the compounds can be measured by time kill analysis using the broth microdilution method ^* . In time kill assays for Staphylococcus aureus and methicillin resistant S. aureus (MRSA), the starting inoculum of S. aurues and MRSA is 10 ⁶ CFU / mL in Mueller Hinton broth. Antibacterial compounds were used at concentrations of 0.1 to 10 fold MIC (ie IC ₉₀ determined in microtiter plate assay). Wells not provided with antibacterial agent consisted of culture propagation control. Plates containing microorganisms and test compounds were incubated at 37 ° C. After 0, 4, 24 and 48 hours of inoculation, samples were plated (200 μl) on Muller Hinton agar by serial dilution (10 ⁻¹ to 10 ⁻⁶ ) in sterile PBS. Plates were incubated at 37 ° C. for 24 hours and colony counts measured. Death curves can be plotted by plotting log ₁₀ CFU per ml over time. Bactericidal effects are usually defined as a 3-log ₁₀ reduction in CFU number per ml compared to untreated inoculum. Colonies were counted at the highest dilution used for a series of dilutions and platings to remove any potential residual drug. No residual was observed at dilutions of 10 ⁻² used for plating. This results in a detection limit of 5 × 10 ² CFU / ml or <2.7 log CFU / ml.

^* Zurenko, GE et al. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents Chemother . 40 , 839-845 (1996).

Measurement of ATP Levels in Cells

To analyze changes in total cell ATP concentrations (using ATP bioluminescence kit, Roche), S. aureus (ATCC29213) stock cultures were grown in 100 ml of Mueller Hinton flasks and stirred-incubator for 24 hours at 37 ° C. Analysis was performed by incubation at 300 rpm). OD ₄₀₅ nm was measured and CFU / mL was calculated. Cultures were diluted to 1 × 10 ⁶ CFU / mL (final concentration for ATP measurement: 1 × 10 ⁵ CFU / 100 μl per well) and test compounds were added at 0.1-10 fold MIC (ie IC ₉₀ determined in microtiter plate assay). . These tubes were incubated at 37 ° C. at 300 rpm for 0, 30, 60 minutes. A 0.6 ml bacterial suspension from the snap-cap tube was used and added to a new 2 ml eppendorf tube. 0.6 ml of cell lysate was added (Roche kit), vortexed at maximum speed, and incubated at room temperature for 5 minutes. Cooled on ice. The luminometer was warmed to 30 ° C (Luminoskan Ascent Labsystems with injector). One column (= 6 wells) was filled with 100 μl of the same sample. 100 μl of luciferase reagent was added to each well using an injector system. Luminescence was measured for 1 second.

Table 2 : IC ₉₀ values (μg / mL) determined according to microtiter plate analysis

BSU43639 means Bacillus substilis (ATCC43639); ECO 25922 means Escherichia coli (ATCC25922); ECO 35218 means Escherichia coll (ATCC35218), ECO 1403 means Escherichia coli (ATCC 1403), and EFA 14506 means Enterococcus faecalis (ATCC14506); EFA 29212 means Enterococcus faecalis (ATCC29212); LMO 49594 means Listeria monocytogenes (ATCC49594); PAE 27853 means Pseudomonas aeruginosa (ATCC27853); SMU 33402 means Streptococcus mutans (ATTC33402); SPN 6305 means Streptococcus pneunoniae (ATCC6305); SPY 8668 means Streptococcus pyogene (ATCC8668); STA 43300 means Staphylococcus aureus (ATCC43300); STA 25923 means Staphylococcus aureus (ATTC29213); STA 29213 means Staphylococcus aureus (ATCC29213); STA RMETH means methicillin resistant Staphylococcus aureus (MRSA) (a clinical isolate from Antwerp University).

ATCC stands for American type tissue culture.

Claims (21)

Compounds of formulas (Ia) and (Ib), pharmaceutically acceptable acid or base addition salts thereof, quaternary amines, stereochemical isomers, tautomers or N, for the preparation of a medicament for the treatment of bacterial infections except mycobacterial infection Uses in the form of oxides:

Where R ¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; p is an integer of 1, 2 or 3; R ² is hydrogen; Alkyl; Hydroxy; Mercapto; Amino or mono or di (alkyl) amino or formula

Alkyloxy optionally substituted by radicals of which Z is CH ₂ , CH-R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an optional bond; Alkyloxyalkyloxy; Alkylthio; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two substituents independently selected from the group consisting of alkyloxy, Ar, Het, morpholinyl and 2-oxopyrrolidinyl, respectively has exist); Ar; Het or expression

Is a radical of which Z is CH ₂ , CH—R ¹⁰ , O, S or NR ¹⁰ , t is an integer of 1 or 2, and the dotted line is an arbitrary bond; R ³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl; q is an integer of 0, 1, 2, 3 or 4; X is a direct bond or CH ₂ ; R ⁴ and R ⁵ are each independently hydrogen, alkyl or benzyl; R ⁴ and R ⁵ together with N, to which they are attached, are each alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl or pyri Pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, optionally substituted by midinyl, Forms a radical selected from the group consisting of triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl Can do it; R ⁶ is hydrogen or

Is a radical of wherein s is an integer of 0, 1, 2, 3 or 4, r is an integer of 1, 2, 3, 4 or 5, R ¹¹ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl, or two adjacent R ¹¹ radicals together may form naphthyl with the phenyl ring to which they are attached ; R ⁷ is hydrogen, alkyl, Ar or Het; R ⁸ is hydrogen or alkyl; R ⁹ is oxo; R ⁸ and R ⁹ together form a radical —CH═CH—N =; R ¹⁰ is hydrogen, alkyl, hydroxyl, aminocarbonyl, mono- or di (alkyl) aminocarbonyl, Ar, Het, alkyl substituted by 1 or 2 Het, or substituted by 1 or 2 Ar Alkyl, Het-C (= 0)-or Ar-C (= 0)-; Alkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein each carbon atom may be optionally substituted by hydroxy, alkyloxy or oxo; Ar is hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, alkylcarbonyl, aminocarbonyl, mor Selected from the group consisting of phenyl, naphthyl, acenaphthyl and tetrahydronaphthyl optionally substituted by one, two or three substituents independently selected from the group consisting of polyyl and mono- or dialkylaminocarbonyl Homocycle; Het is N -phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, Monocyclic heterocycles selected from the group consisting of pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothia Bicyclic heterocycle selected from the group consisting of zolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxylyl and benzo [1,3] dioxolyl ego; Each monocyclic and bicyclic heterocycle may be optionally substituted on the carbon atom by 1, 2 or 3 substituents each independently selected from the group consisting of halo, hydroxy, alkyl and alkyloxy; Halo is a substituent selected from the group consisting of fluoro, chloro, bromo and iodo; Haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Or cyclic saturated hydrocarbon radicals having 3 to 6 carbon atoms; Or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; Wherein at least one carbon atom is substituted by at least one halo atom, only, When R ⁷ is hydrogen, Radical

May be present at the 4 position of the quinoline ring. 2. Use according to claim 1, wherein R ¹ is hydrogen, halo or Het. 3. Use according to claim 2, wherein R ¹ is halo. 4. Use according to any one of claims 1 to 3, wherein p is 1. The compound of claim 1, wherein R ² is alkyloxy; Het; Ar; Mono or di (alkyl) amino, wherein alkyl may be optionally substituted by one or two Ar substituents; expression

Radicals, wherein Z is NR ¹⁰ and t is an integer of 2; Amino or mono or di (alkyl) amino or formula

And is an alkyloxy substituted by a radical of which Z is CH ₂ and t is an integer of 2. 6. Use according to claim 5, wherein R ² is alkyloxy. The use according to any one of claims 1 to 6, wherein R ³ is naphthyl, phenyl or Het, each optionally substituted with one or two substituents. 8. Use according to claim 7, wherein R ³ is naphthyl, phenyl, 3,5-dihalophenyl, thienyl, furanyl or benzofuranyl. The use according to any one of claims 1 to 8, wherein q is one. The use according to any one of claims 1 to 9, wherein R ⁴ and R ⁵ are each independently alkyl. The use according to any one of claims 1 to 10, wherein R ⁶ is benzyl or phenyl. Use according to any of the preceding claims, wherein R ⁷ is hydrogen. 13. Use according to any one of the preceding claims, wherein X is a direct bond. 13. Use according to any of the preceding claims, wherein X is CH ₂ . Use according to any one of claims 1 to 14, wherein the compound is a compound of formula (la). Use according to any one of claims 1 to 15, wherein the bacterial infection is an infection with Gram-positive bacteria. A combination of (a) a compound of formula (la) or (lb) as defined in any one of claims 1 to 15 and (b) at least one other antibacterial agent other than an antimicrobial agent. A pharmaceutically acceptable carrier and a therapeutically effective amount of an active ingredient as (a) a compound of formula (la) or (lb) as defined in any one of claims 1 to 15 and (b) an antimycobacterial agent A pharmaceutical composition comprising at least another antibacterial agent. Use of the combination of claim 17 or the pharmaceutical composition of claim 18 for treating a bacterial infection. Combination formulations for simultaneous, separate or sequential use in the treatment of bacterial infections other than (a) compounds of formula (Ia) or (Ib) as defined in any of claims 1 to 15 and (b) antimycobacterial agents Products containing at least one other antibacterial agent.

And pharmaceutically acceptable acid or base addition salts, quaternary amines, stereochemical isomers, tautomers or N-oxide forms thereof.